Mdm2 and p53 interaction inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

 

The technical field to which the invention relates

The present invention relates to compounds and compositions containing these compounds acting as inhibitors of the interaction between MDM2 and p53, in particular as modulators of the interaction between MDM2-proteasome. The invention also relates to a method of obtaining the disclosed compounds and compositions and methods of use thereof, for example, as pharmaceuticals.

p53 is a tumor suppressor protein that plays a major role in regulating the balance between cell proliferation and stop cell growth/apoptosis. In normal conditions the half-life of p53 is very short, and consequently, the level of p53 in the cells is low. However, in response to damage cellular DNA or cellular stress (e.g., activation of an oncogene, the destruction of telomeres, hypoxia) levels of p53 increase. These increased levels of p53 leads to activation of transcription of several genes that control cell, or to stop growth, or apoptosis. Thus, an important function of p53 must be the prevention of the uncontrolled proliferation of damaged cells and, thus, protecting the body from cancer.

MDM2 is a key negative regulator of p53 function. It forms a negative auto-regulatory loop by binding Amin the end transactionbased domain of p53, and thus, MDM2 as inhibits the ability of p53 to activate transcription and directs p53 proteolytic cleavage. In normal conditions this regulatory loop is responsible for maintaining low levels of p53. However, in tumors with p53 wild-type equilibrium concentration of active p53 can increase due to counter the interaction between MDM2 and p53. Another effect of MDM2 is also required for the destruction of p53, as evidenced by the accumulation ubiquitarian p53, when phosphorylation in the Central domain of HDM2 is cancelled (Blattner et al., Hypophosphorylation of Mdm2 augments p53 stability. (2002) Mol. Cell. Biol., 22, 6170-6182). The Association of HDM2 with different subunits of the 26S proteasome, such as S4, S5a, S6a and S6b (3rd Symposium on Mdm2, Sept. 2005, Konstanz, Germany), may play a key role in this process. Thus, the concentration of p53 can also increase due to modulation of the interaction between MDM2-proteasome. This will lead to the restoration of p53-mediated proapoptotic and antiproliferative action in these tumor cells. Antagonists of MDM2 can be even antiproliferative effects in tumor cells that lack functional p53.

This circumstance puts HDM2 protein in the position attractive target for the development of anti-cancer therapy.

MDM2 is a cell protooncogenes. The overexpression of MDM2 observed is t when the number of cancer diseases. MDM2 sverkhekspressiya in various tumors due to gene amplification or enhanced transcription or translation. The mechanism by which MDM2 amplification promotiom tumorigenesis, at least partially associated with its interaction with p53. In cells, sverkhekspressiya MDM2, the protective function of p53 is blocked, and therefore the cells are unable to respond to DNA damage or cellular stress increased levels of p53, leading to stoppage of growth and/or apoptosis of cells. Thus, after DNA damage and/or cellular stress cells, sverkhekspressiya MDM2, are free to continue to proliferate and take oncogenic phenotype. In such conditions, disruption of the interaction between p53 and MDM2 could release p53 and, thus, to prevent the normal passage of signals stop the growth and/or apoptosis.

MDM2 can also have separate functions, in addition to inhibition of p53. A number of substrates MDM2 quickly expands. For example, it is shown that MDM2 interacts directly with pRb-regulated transcription factor E2F1/DP1. This interaction may be critical for p53-independent oncogenic activities of MDM2. Domain E2F1 shows a striking similarity with the MDM2-binding domain of p53. Because of the interaction of MDM2 with p53 and E2F1 localized on MDM2 in the same binding site, it can be expected that antagonists of MDM2/p53 will not tol is to activate the cellular p53, but also modulate the activity of E2F1, which is usually cancelled in tumor cells. Other basic examples of substrates include MDM2 P63, R, p21waf1,cip1.

Also therapeutic effectiveness of damaging DNA, currently used (chemotherapy and radiotherapy)may be limited through the negative regulation of p53, MDM2. So, if the inhibition of p53 by MDM2 type of feedback is interrupted, raising levels of functional p53 will improve therapeutic efficacy of such funds due to restoration of function of p53 wild-type, leading to apoptosis and/or reversion of p53-associated drug resistance. It is shown that the combination of MDM2 inhibition and treatment with DNA damage in vivo leads to synergistic antitumor effect (Vousden K.H., Cell, Vol.103, 691-694, 2000).

Thus, disruption of the interaction between MDM2 and p53 presents an approach for therapeutic intervention in tumors with wild type p53 or mutant p53 can induce antiproliferative effects in tumor cells that lack functional p53, and moreover, may make tumor cells sensitive to chemotherapy and radiation therapy.

Background of invention

In WO 2006/032631 disclosed inhibitors of the interaction between MDM2 and p53, are applicable, inter alia, in the treatment op the Halsey and enhancing the effectiveness of chemotherapy and radiation therapy.

Compounds of the present invention differ in structure from the compounds of WO 2006/032631 when comparing additional substituent R20on the Central phenyl cycle.

In WO 2007/107543 also disclosed inhibitors of the interaction between MDM2 and p53, are applicable, inter alia, in the treatment of tumors and enhance the effectiveness of chemotherapy and radiation therapy.

Unexpected, but significant structural modification of the present invention does not reduce the activity of the compounds of the present invention. Therefore, the invention provides additional useful a number of effective and strong small molecules which inhibit the interaction between MDM2 and p53, and which may be drugs.

Description of the invention

The present invention relates to compounds and compositions and methods for inhibition of the interaction between MDM2 and p53 for the treatment of proliferative diseases, including tumors and cancer. In addition, the compounds and compositions of the present invention is applicable to enhance the effectiveness of chemotherapy and radiation therapy.

Accordingly in one aspect the invention relates to the compound of formula (I)

including any stereochemical isomeric form, where

m is 0, 1 or 2, and when m is 0, this then implies a direct link;

n is 0, 1, 2 or 3, and when n is 0 then implies a direct link;

p is 0 or 1, and when p is 0, this then implies a direct link;

s is 0 or 1 and when s is 0, this then implies a direct link;

t is 0 or 1, and when t is 0, this then implies a direct link;

X represents C(=O) or CHR8where

R8selected from hydrogen; C1-6-alkyl; C3-7-cycloalkyl; -C(=O)-NR17R18; carboxyl, aryl-C1-6-allyloxycarbonyl; heteroaryl; heteroarylboronic; heteroaryl-C1-6-allyloxycarbonyl; piperazinylcarbonyl; pyrrolidinyl; piperidinylcarbonyl; C1-6-allyloxycarbonyl; C1-6of alkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl; C3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl; piperazinylcarbonyl, substituted Deputy selected from hydroxy, hydroxy-C1-6-alkyl, hydroxy-C1-6-alkyloxy-C1-6-alkyl; pyrrolidinyl, substituted hydroxy-C1-6-alkyl; and piperidinylcarbonyl substituted by one or two substituents selected from hydroxy, C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl(dihydroxy)-C1-6-alkyl and C1-6-alkyloxy(hydroxy)-C1- -alkyl;

R17and R18choose, each independently, from hydrogen, C1-6-alkyl, di(C1-6-alkyl)amino-C1-6-alkyl, aryl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, hydroxy-C1-6-alkyl(C1-6-alkyl) or hydroxy-C1-6-alkyl(aryl-C1-6-alkyl);

represents-CR9=C<, and then the dotted line represents a bond, -C(=O)-CH<, -C(=O)-N<, -CHR9-CH< or-CHR9-N<, where each R9represents independently hydrogen or C1-6-alkyl, or where R9together with one of R2or R20forms a direct link;

R1represents hydrogen; aryl; heteroaryl; C1-6-allyloxycarbonyl; C1-12-alkyl or C1-12-alkyl, substituted by one or two substituents selected independently from hydroxy, aryl, heteroaryl, amino, C1-6-alkyloxy, mono - or di(C1-6-alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil,1-6-alkylpiperazine, aryl-C1-6-alkylpiperazine, heteroaryl-C1-6-alkylpiperazine,3-7-cycloalkylcarbonyl and C3-7-cycloalkyl-C1-6-alkylpiperazine;

R2and R20choose, each independently, from

of halogen, hydroxy, cyano, nitro, carboxyl;

polyhalogen-C1-6 -alkyl, polyhalogen-C1-6-alkyloxy;

With1-6-alkyl, C3-7-cycloalkyl,2-6-alkenyl, aryl, heteroaryl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-7-cycloalkyl-C1-6-alkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil,1-6-alkyloxy, aryloxy, heteroaromatic,1-6-alkylthio, aaltio, heteroaromatic,1-6-alkylsulphonyl,3-7-cycloalkylcarbonyl, arylcarbamoyl, heteroarylboronic,1-6-allyloxycarbonyl,3-7-cycloalkylcarbonyl, aryloxyalkyl, heteroarylboronic,1-6-alkylcarboxylic,3-7-cycloalkylcarbonyl, arylcarboxylic or heteroarylboronic, and any of these groups optionally and independently substituted by one or more, preferably one or two, substituents selected from halogen, hydroxy, cyano, nitro, carboxyl, amino, mono - or di(C1-6-alkyl)amino, C1-6-alkyl, polyhalogen-C1-6of alkyl, aryl, heteroaryl,1-6-alkyloxy,1-6-alkylsulphonyl,1-6-allyloxycarbonyl and C1-6-alkylcarboxylic; and

-(CH2)w-C(=O))yNR21R22where

w is equal to 0, 1, 2, 3, 4, 5 or 6, and when w is 0, this then implies a direct link;

y is 0 or 1, and when y is 0, then refers to direct the linkage;

R21and R22choose, each independently, from hydrogen, C1-6-alkyl, C3-7-cycloalkyl,1-6-alkylcarboxylic and aryl-C1-6-alkylsulphonyl, and any of these groups optionally and independently substituted by one or more, preferably one or two, substituents selected from halogen, hydroxy, amino, mono - or di(C1-6-alkyl)amino, C1-6-alkyl, polyhalogen-C1-6-alkyl, C1-6-alkyloxy, aryl and heteroaryl;

or R21and R22together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl or piperazinil, and any of these groups optionally and independently substituted by one or more, preferably one or two, substituents selected from C1-6-alkyl, polyhalogen-C1-6-alkyl, C1-6-alkyloxy,3-7-cycloalkyl,3-7-cycloalkyl-C1-6-alkyl, aryl-C1-6-alkyl and heteroaryl-C1-6-alkyl;

or R2and R20together with the phenyl cycle to which they are attached, form naphthalenyloxy group, optionally substituted by one or more, preferably one or two, substituents selected each independently from halogen, hydroxy, amino, mono - or di(C1-6-alkyl)amino, C1-6-alkyl, polyhalogen-C1-6of alkyl, With1-6-alkyloxy, aryl and heteroaryl;

or R2and R20together form a bivalent radical of the formula -(CH2)b-where b is equal to 3, 4 or 5, optionally substituted by one or more, preferably one or two, substituents selected from halogen, hydroxy, amino, mono - or di(C1-6-alkyl)amino, C1-6-alkyl, polyhalogen-C1-6-alkyl, C1-6-alkyloxy, aryl and heteroaryl;

or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct link;

R3represents hydrogen; C1-6-alkyl; heteroaryl; C3-7-cycloalkyl; C1-6-alkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl; or (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl;

R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, hydroxy-C1-6-alkyl, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxy, amino, C2-6alkenyl or1-6-alkyloxy; or

R4and R5together form a bivalent radical selected from methylenedioxy or Ethylenedioxy;

R6represents hydrogen, C1-6-allyloxycarbonyl or1-6-alkyl;

when R is Aven 1, then R7represents hydrogen, aryl-C1-6-alkyl, hydroxy or heteroaryl-C1-6-alkyl;

Z represents a radical selected from the

where

R10or R11choose, each independently, from hydrogen, halogen, hydroxy, amino, C1-6-alkyl, nitro, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, tetrazol-C1-6of alkyl, aryl, heteroaryl, aryl-C1-6-alkyl, heteroaryl-C1-6of alkyl, aryl(hydroxy)-C1-6-alkyl, heteroaryl(hydroxy)-C1-6-alkyl, arylcarbamoyl, heteroarylboronic,1-6-alkylsulphonyl, aryl-C1-6-alkylsulphonyl, heteroaryl-C1-6-alkylsulphonyl,1-6-alkyloxy,3-7-cycloalkylcarbonyl,3-7-cycloalkyl(hydroxy)-C1-6-alkyl, aryl-C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyloxy-C1-6-alkyl, C1-6-alkylcarboxylic-C1-6-alkyl, C1-6-allyloxycarbonyl-C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl-C2-6-alkenyl,1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl,1-6-alkylcarboxylic, aminocarbonyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, hydroxy what arbonia, hydroxycarbonyl-C1-6-alkyl, and -(CH2)v-(C(=O))r-(CHR19)u-NR13R14where

v is equal to 0, 1, 2, 3, 4, 5 or 6, and when v is 0, this then implies a direct link;

r is 0 or 1, and when r is 0, this then implies a direct link;

u = 0, 1, 2, 3, 4, 5 or 6, and when u is equal to 0, this then implies a direct link;

R19represents hydrogen or C1-6-alkyl;

R13and R14choose, each independently, from hydrogen; C1-12-alkyl; C1-6-alkylcarboxylic; C1-6-alkylsulfonyl; aryl-C1-6-alkylcarboxylic; C3-7-cycloalkyl; C3-7-cycloalkylcarbonyl; -(CH2)k-NR15R16;1-12of alkyl, substituted Deputy selected from hydroxy, hydroxycarbonyl, cyano, C1-6-allyloxycarbonyl,1-6-alkyloxy, aryl or heteroaryl; or (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl, amino, aryl-C1-6-alkyl, heteroaryl or heteroaryl-C1-6-alkyl; or

R13and R14together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl, piperazinil or piperazinil, substituted Deputy, selected from C1-6-alkyl, aryl-C1-6-alkyl, aryl-C1-6-allyloxycarbonyl, heteroaryl-C1-6of alkyl, With3-7-cycloalkyl and C3-7-cycloalkyl-C1-6-alkyl; where

k is equal to 0, 1, 2, 3, 4, 5 or 6, and when k is 0, this then implies a direct link;

R15and R16choose, each independently, from hydrogen; C1-12-alkyl; aryl-C1-6-allyloxycarbonyl; C3-7-cycloalkyl; C1-12of alkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl and heteroaryl; and (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl; or

R15and R16together with the nitrogen atom to which they are attached, form morpholinyl, piperazinil or piperazinil, substituted C1-6-allyloxycarbonyl;

R12represents hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C1-6-alkyl, substituted Deputy selected from hydroxy, amino, C1-6-alkyloxy and aryl; or (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and C1-6-alkyloxy;

aryl represents phenyl or naphthalenyl;

each phenyl or naphthalenyl may be optionally substituted by one, two or three substituents selected each independently from halogen, hydroxy, C1-6-alkyl, amino, polyhalogen-C1-6-alkyl and C1-6 -alkyloxy; and

each phenyl or naphthalenyl may be optionally substituted bivalent radical selected from methylenedioxy, Ethylenedioxy;

heteroaryl represents pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;

each pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl may be optionally substituted by one, two or three substituents selected each independently from halogen, hydroxy, C1-6-alkyl, amino, polyhalogen-C1-6of alkyl, aryl, aryl-C1-6-alkyl or C1-6-alkyloxy; or

each pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl may be optionally substituted bivalent radical selected from methylenedioxy, Ethylenedioxy;

its N-oxide form, its salts accession or their solvate.

The compounds of formula (I) can also exist in their tautomeric forms. Although such shape is not specified clearly in the above formula, it is understood that they are included in the scope of the present invention.

A number of terms used in the above definitions and hereinafter in this description, explained below. Such terms can be used the AK any, or complex terms.

Used in this description, the term "halogen" is shared by fluorine, chlorine, bromine and iodine. "C1-6-Alkyl" denotes a linear or branched saturated hydrocarbon radicals with 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl etc. "C1-12-Alkyl" includes1-6-alkyl and higher linear or branched homologues with 7-12 carbon atoms, such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc. the Term "hydroxy-C1-6-alkyl" refers to C1-6the alkyl having values above, where one or more (e.g. one, two, three or more hydrogen atoms of the specified1-6-alkyl substituted Deputy hydroxyl. The terms "polyhalogen-C1-6-alkyl" and "polyhalogen-C1-6-alkyloxy" refer respectively to C1-6the alkyl or C1-6-alkyloxy that have values that are above, where one, two or more hydrogen atoms of the specified1-6-alkyl or C1-6-alkyloxy replaced by the same or different galactosaminidase; the corresponding terms "polyhalogen-C1-6-alkyl" and "polyhalogen-C1-6-alkyloxy also cover peralagan-C1-6-alkyl and peralagan-C1-6-alkyloxy, i.e. With1-6-alkyl or C1-6-alkyloxy having values, above, where all the hydrogen atoms of the specified1-6-alkyl or C1-6-alkyloxy replaced by the same or different galactosaminidase, for example, trihalomethyl determines methyl containing three identical or different halogenosilanes, such as, for example, trifluoromethyl, or, for example, trihalomethane determines metiloksi containing three identical or different halogenosilanes, such as, for example, cryptometrics. "C2-6Alkenyl" specifies a linear or branched hydrocarbon radicals containing one or more double bonds, preferably one double bond and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl etc. "C3-7-Cycloalkyl" includes acyclic saturated or unsaturated hydrocarbon group having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl etc. Preferably3-7-cycloalkyl includes alicyclic saturated hydrocarbon group having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.

The term "salt of the merger" includes salts which the compounds of formula (I) can form with an organic or inorganic base is s, such as amines, bases, alkali metal and alkaline earth metal base or Quaternary ammonium bases, or with organic or inorganic acids such as mineral acids, sulfonic acid, carboxylic acid or phosphorus-containing acid.

The term "salt of the accession also includes pharmaceutically acceptable salts, metal complexes and their salts, which can form compounds of formula (I).

The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of the accession of acids or bases. Pharmaceutically acceptable salts of the accession of acids or bases specified in the description above, include therapeutically active non-toxic form of salts accession of acids and bases that can form the compounds of formula (I). The compounds of formula (I)have basic properties can be converted into their pharmaceutically acceptable salts accession acids, treating the specified form the Foundation of the corresponding acid. Appropriate acids comprise, for example, inorganic acid, such as halogen acids, for example hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, oxiana, rocna, pyruvic, oxalic, malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and the like acid.

The compounds of formula (I)having acidic properties may be converted into their pharmaceutically acceptable salts attaching grounds, the processing of the specified acid form with a suitable organic or inorganic base. The corresponding salt forms of the bases include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example salt, benzathine, N-methyl-D-glucamine, geranamine, and salts with amino acids such as, for example, arginine, lysine, etc.

Preferably, the term "salt accession" means pharmaceutically acceptable salt accession acid or base.

The term "metal complexes" refers to a complex formed by the compound of formula (I) and one or more organic or inorganic salts of metals. Examples of these organic or inorganic salts include the halides, nitrates, sulfates, phosphates, acetates, triptoreline, trichloracetate, PR is pionate, the tartratami, sulfonates, for example methylsulfonate, 4-methylphenylsulfonyl, salicylates, benzoate and other metals of the second main group of the Periodic system of elements, such as salts of magnesium or calcium, third or fourth main group, e.g. aluminum, tin, lead, and the first to eighth transition group of the Periodic system, such as, for example, chromium, manganese, iron, cobalt, Nickel, copper, zinc, etc.

The term "stereochemical isomeric forms of the compounds of formula (I)used in this description, defines all possible compounds consisting of the same atoms connected by the same sequence of relationships, but having different three-dimensional structures which are not interchangeable, which can form compounds of formula (I). If not included or indicated, the chemical designation of compounds comprises a mixture of all possible stereochemical isomeric forms, which specified the connection can have. This mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the compounds. Assumes that all stereochemical isomeric forms of the compounds of formula (I) in a clean form or in mixture with each other included in the scope of the present invention.

Of particular interest are compounds of formula (I), to the which are stereochemical clean.

Pure stereoisomeric forms of the compounds and intermediates described in this description are defined as isomers, essentially free from other enantiomeric or diastereoisomeric forms of the same basic molecular structure of these compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediates having stereometry excess of at least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomers) and 100% (i.e. 100% of one isomer and no other), more preferably compounds or intermediates having stereometry excess of 90% to 100%, even more preferably having stereometry excess from 94% to 100% and most preferably having stereometry excess from 97% to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood in a similar way, but with respect to the enantiomeric excess and thus to diastereomeric excess discussing mixture.

The N-Oxide forms of the compounds of formula (I) include compounds of formula (I)in which one or several tertiary nitrogen atoms oxidized to the so-called N-oxide, in particular N-oxides, in which the N-oxidized are one or more nitrogen atoms of the piperidine, piperazine or pyridazinyl.

The compounds of formula (I) can be converted into the corresponding N-oxide forms following known in the art procedures for conversion of trivalent nitrogen into its N-oxide form. The above reaction of N-oxidation, as a rule, can be realized by the interaction of the educt of the formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metals or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include, among other things, nagkalat, such as, for example, derbentina acid or halogen-substituted derbentina acid, such as 3-chloroperbenzoic acid, paracalanidae acid, for example purakayastha acid, alkylhydroperoxide, such as tertBUTYLPEROXY. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

The compounds of formula (I) may form a solvate, for example, with water (i.e. hydrates) or common organic solvents, for example alcohols. Used in this description, the term "MES" means the physical and the Association of compounds of formula (I), and their salts with one or more solvent molecules. Physical Association involves varying degrees of ionic and other communications, including hydrogen bonds. In some cases, the MES can be identified, for example, when one or more molecules of solvent introduced into the crystal lattice of the crystalline solid. It is implied that the term "MES" covers a solvate both in solution phase and insoluble solvate. Non-restrictive examples of suitable solvate includes hydrates, ethanolate, methanolate etc.

In addition, the compounds of the present invention may be amorphous or may have one or more crystalline polymorphic forms, implying that such forms are included within the scope of the invention.

The invention covers any and all isotopes of atoms present in the compounds according to the invention. For example, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include13C and14C.

Whenever used hereinafter in this specification, the term "compounds of formula (I), we mean that it also includes the N-oxide forms, the salt of the accession of acids or bases, in particular pharmaceutically acceptable salts accession acids or bases, solvate and all stereoisomeric forms of these compounds of formula (I).

<> The first group of compounds of interest (hereinafter called the group "G1"), consists of those compounds of formula (I), which applies one or more or all of the following limitations:

a) X represents C(=O) or CHR8where

R8selected from hydrogen; C1-6-alkyl; C3-7-cycloalkyl; aminocarbonyl; mono - or di(C1-6-alkyl)aminocarbonyl; carboxyl; aryl-C1-6-allyloxycarbonyl; heteroaryl-C1-6-allyloxycarbonyl; C1-6-allyloxycarbonyl; C1-6of alkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl; or (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl;

b) R1represents hydrogen; aryl; heteroaryl; C1-12-alkyl or C1-12-alkyl, substituted by one or two substituents selected independently from hydroxy, aryl, heteroaryl, amino, C1-6-alkyloxy, mono - or di(C1-6-alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil,1-6-alkylpiperazine, aryl-C1-6-alkylpiperazine, heteroaryl-C1-6-alkylpiperazine,3-7-cycloalkylcarbonyl and C3-7-cycloalkyl-C1-6-alkylpiperazine;

(C) R3represents hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C1-6-alkyl,substituted Deputy selected from hydroxy, amino, aryl and heteroaryl; or (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl;

d) R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, hydroxy-C1-6-alkyl, polyhalogen-C1-6-alkyl, hydroxy, amino, C2-6alkenyl or1-6-alkyloxy; in particular, R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, polyhalogen-C1-6-alkyl, hydroxy, amino or1-6-alkyloxy;

e) R4and R5together form a bivalent radical selected from methylenedioxy or Ethylenedioxy;

f) R6represents hydrogen or C1-6-alkyl;

g) when p is equal to 1, then R7represents hydrogen, aryl-C1-6is alkyl or heteroaryl-C1-6-alkyl;

h) Z is a radical selected from (a-1), (a-2), (a-3), (a-4) and (a-5);

i) R10or R11choose, each independently, from hydrogen; hydroxyl; amino; C1-6-alkyl; nitro; polyhalogen-C1-6-alkyl; cyano; cyano-C1-6-alkyl; tetrazolo-C1-6-alkyl; aryl; heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; aryl(hydroxy)-C1-6-alkyl; heteroaryl(hydroxy)-C1-6-alkyl; arylcarbamoyl; heteroarylboronic; aryl-C1-6-Alki is carbonyl; heteroaryl-C1-6-alkylcarboxylic; C1-6-alkyloxy; C1-6-alkyloxy-C1-6-alkyl; C1-6-allyloxycarbonyl; C1-6-alkylcarboxylic; aminocarbonyl; hydroxy-C1-6-alkyl; amino-C1-6-alkyl; hydroxycarbonyl; hydroxycarbonyl-C1-6-alkyl, and -(CH2)v-(C(=O))r-(CH2)u-NR13R14;

j) R13and R14choose, each independently, from hydrogen; C1-12-alkyl; C3-7-cycloalkyl; -(CH2)k-NR15R16;1-12of alkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl or heteroaryl; or (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl;

k) R13and R14together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl, piperazinil or piperazinil, substituted Deputy, selected from C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-7-cycloalkyl and C3-7-cycloalkyl-C1-6-alkyl;

l) R15and R16choose, each independently, from hydrogen; C1-12-alkyl; C3-7-cycloalkyl; C1-12of alkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy is, aryl and heteroaryl; and (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl; in particular, R15and R16choose, each independently, from hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C1-12of alkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl and heteroaryl; and (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl;

m) heteroaryl represents pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl; and each pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl may be optionally substituted by one, two or three substituents selected each independently from halogen, hydroxy, C1-6-alkyl, amino, polyhalogen-C1-6-alkyl and C1-6-alkyloxy; and

n) each pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl may be optionally substituted bivalent radical selected from methylenedioxy or Ethylenedioxy.

The second group of compounds of interest (hereinafter called the by the group "G2"), consists of those compounds of formula (I), which applies one or more or all of the following limitations:

a) n is 0, 1 or 2;

b) p is 0;

(C) X represents C(=O) or CHR8preferably CHR8where

R8represents hydrogen, aminocarbonyl, aryl-C1-6-allyloxycarbonyl or1-6-alkyl, substituted hydroxy;

d)represents-CR9=C< or-CHR9-CH<;

e) R1represents hydrogen, C1-12-alkyl or C1-12-alkyl, substituted heteroaryl;

f) R3represents hydrogen or C1-6-alkyl;

g) R4and R5represent, each independently, hydrogen, halogen or1-6-alkyloxy;

h) Z is a radical selected from (a-1), (a-2), (a-3) and (a-4);

i) R10or R11choose, each independently, from hydrogen, hydroxy, amino, C1-6-alkyl, nitro, polyhalogen-C1-6-alkyl, cyano, aryl, aryl-C1-6of alkyl, aryl(hydroxy)-C1-6-alkyl, arylcarbamoyl,1-6-alkyloxy,1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl, aminocarbonyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, hydroxycarbonyl and -(CH2)v-(C(=O))r-(CH2)u-NR13R14;

j) v is 0 or 1;

k) r is 0 or 1;

l) u Rawa is 0;

m) R13and R14choose, each independently, from hydrogen, C1-6-alkyl, -(CH2)k-NR15R16and C1-12of alkyl, substituted hydroxy;

n) R13and R14together with the nitrogen atom to which they are attached, can form pyrrolidinyl;

o) k = 2;

R) R15and R16each independently represent a1-6-alkyl;

q) aryl represents phenyl or phenyl substituted by halogen; and

r) heteroaryl represents pyridinyl or indolyl.

The third group of compounds of interest (hereinafter called the group "G3"), consists of those compounds of formula (I), which applies one or more or all of the following limitations:

a) m is 0 or 2;

b) n is 0, 2 or 3;

C) R is equal to 1;

d) s is equal to 1;

e) t is equal to 1;

f) X represents C(=O);

g)represents-C(=O)-CH<, -C(=O)-N<, -CHR9-CH< or-CHR9-N<;

h) R1represents aryl; heteroaryl; C1-6-allyloxycarbonyl; C1-12-alkyl or C1-12-alkyl, substituted by one or two substituents selected independently from hydroxy, aryl, heteroaryl, amino, C1-6-alkyloxy, mono - or di(C1-6-alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil,1-6-alkylpiperazine, aryl-C1-6-Ala is piperazinyl, heteroaryl-C1-6-alkylpiperazine,3-7-cycloalkylcarbonyl and C3-7-cycloalkyl-C1-6-alkylpiperazine;

i) R3represents a C1-6-alkyl; C3-7-cycloalkyl; C1-6-alkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl; or (C3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl;

j) R4and R5represent, each independently, With1-6-alkyl, polyhalogen-C1-6-alkyl, hydroxy-C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxyl, amino or2-6alkenyl; in particular1-6-alkyl, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxy or amino;

k) R4and R5together form a bivalent radical selected from methylenedioxy or Ethylenedioxy;

l) R6represents a C1-6-allyloxycarbonyl or1-6-alkyl;

m) R7represents hydrogen, aryl-C1-6-alkyl, hydroxy or heteroaryl-C1-6-alkyl; and

n) Z is a radical selected from (a-1), (a-3), (a-4), (a-5), (6), (7) and (a-8).

The fourth group of compounds of interest (hereinafter called the group "G4"), consists of those compounds of formula (I), which applies one or more or all of the following limitations:

a) X t is made by a C(=O) or CHR 8preferably CHR8where

R8represents hydrogen, -C(=O)-NR17R18, aryl-C1-6-allyloxycarbonyl,1-6-alkyl, substituted hydroxy, piperazinylcarbonyl, substituted hydroxy, hydroxy-C1-6-alkyl, hydroxy-C1-6-alkyloxy-C1-6-alkyl, pyrrolidinyl, substituted hydroxy-C1-6-alkyl, or piperidinylcarbonyl substituted by one or two substituents selected from hydroxy, C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl(dihydroxy)-C1-6-alkyl or C1-6-alkyloxy(hydroxy)-C1-6-alkyl;

b) R17and R18choose, each independently, from hydrogen, C1-6-alkyl, di(C1-6-alkyl)amino-C1-6-alkyl, aryl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl;

C)represents-CR9=C<, -CHR9-CH< or-CHR9-N<;

d) R1represents hydrogen, heteroaryl,1-6-allyloxycarbonyl,1-12-alkyl or C1-12-alkyl, substituted heteroaryl;

e) R3represents hydrogen, C1-6is alkyl or heteroaryl;

f) R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, hydroxy-C1-6-alkyl, cyano, cyano-C1-6-lkyl, hydroxyl,2-6alkenyl or1-6-alkyloxy; in particular hydrogen, halogen, C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxy or1-6-alkyloxy;

g) when p is equal to 1, then R7represents aryl-C1-6-alkyl or hydroxy;

h) Z is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-7), (8) and (9);

i) R10or R11choose, each independently, from hydrogen, halogen, hydroxy, amino, C1-6-alkyl, nitro, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, tetrazol-C1-6of alkyl, aryl, heteroaryl, heteroaryl-C1-6of alkyl, aryl(hydroxy)-C1-6-alkyl, arylcarbamoyl,1-6-alkylsulphonyl,3-7-cycloalkylcarbonyl,3-7-cycloalkyl(hydroxy)-C1-6-alkyl, aryl-C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyloxy-C1-6-alkyl, C1-6-alkylcarboxylic-C1-6-alkyl, C1-6-allyloxycarbonyl-C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl-C2-6-alkenyl,1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl, aminocarbonyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, hydroxycarbonyl, hydroxycarbonyl-C1-6-alkyl, and -(CH2)v-(C(=O))r-(CHR19) u-NR13R14;

j) v is 0 or 1;

k) u is 0 or 1;

l) R12represents hydrogen or C1-6-alkyl;

m) R13and R14choose, each independently, from hydrogen; C1-12-alkyl; C1-6-alkylcarboxylic; C1-6-alkylsulfonyl; aryl-C1-6-alkylcarboxylic; C3-7-cycloalkylcarbonyl; -(CH2)k-NR15R16;1-12of alkyl, substituted Deputy selected from hydroxy, hydroxycarbonyl, cyano, C1-6-allyloxycarbonyl or aryl;

n) R13and R14together with the nitrogen atom to which they are attached, form morpholinyl, pyrrolidinyl, piperazinil or piperazinil, substituted Deputy, selected from C1-6-alkyl or aryl-C1-6-allyloxycarbonyl;

o) k = 2;

R) R15and R16choose, each independently, from hydrogen, C1-12-alkyl or aryl-C1-6-allyloxycarbonyl; in particular hydrogen, C1-6-alkyl or aryl-C1-6-allyloxycarbonyl;

q) R15and R16together with the nitrogen atom to which they are attached, form morpholinyl, piperazinil or piperazinil, substituted C1-6-allyloxycarbonyl;

r) aryl represents phenyl or phenyl substituted by halogen;

s) heteroaryl represents pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and

t) each feast is dinil, indolyl, oxadiazolyl or tetrazolyl may be optionally substituted by one Deputy, selected from C1-6-alkyl, aryl or aryl-C1-6-alkyl.

The fifth group of compounds of interest (hereinafter called the group "G5"), consists of those compounds of formula (I), which applies one or more or all of the following limitations:

a) m is 0;

b) n is 1 or 2;

C) R 0;

d) s 0;

e) t 0;

f) X is a CHR8;

g) R8represents hydrogen;

h)represents-CR9=C<;

i) R9represents hydrogen or C1-6-alkyl;

j) R1represents hydrogen;

k) R3represents hydrogen;

l) R4and R5represent, each independently, hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6alkenyl or1-6-alkyloxy;

m) R6represents hydrogen;

n) Z is a radical selected from (a-1), (a-2) and (a-4);

o) R10and R11choose, each independently, from hydrogen, hydroxy or hydroxy-C1-6-alkyl;

R) R2and R20choose, each independently, from halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl,1-6-alkyloxy, hydroxy-C1-6-alkyl, -NR21R22where 21represents hydrogen and R22represents a C1-6-alkylsulphonyl; or

R2and R20together with the phenyl cycle to which they are attached, form naphthalenyloxy group, or

one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct connection.

The sixth group of compounds of interest (hereinafter called the group "G6"), consists of those compounds of formula (I) or any subgroup in which

X represents C(=O) or CHR8preferably CHR8and R8represents hydrogen; -C(=O)-NR17R18; aryl-C1-6-allyloxycarbonyl; C1-6-alkyl substituted by hydroxyl; piperazinylcarbonyl substituted by hydroxyl; hydroxy-C1-6-alkyl; hydroxy-C1-6-alkyloxy-C1-6-alkyl; pyrrolidinyl, substituted hydroxy-C1-6-alkyl; or piperidinylcarbonyl substituted by one or two substituents selected from hydroxy, C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl(dihydroxy)-C1-6-alkyl or C1-6-alkyloxy(hydroxy)-C1-6-alkyl;

R17and R18choose, each independently, from hydrogen, C1-6-alkyl, di(C1-6-alkyl)amino-C1-6-alkyl, aryl-C1-6-Alki is a, With1-6-alkyloxy-C1-6-alkyl or hydroxy-C1-6-alkyl;

represents-CR9=C<, -CHR9-CH< or-CHR9-N<;

R1represents hydrogen, heteroaryl,1-6-allyloxycarbonyl,1-12-alkyl or C1-12-alkyl, substituted heteroaryl;

R3represents hydrogen, C1-6is alkyl or heteroaryl;

R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, hydroxy-C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxyl, C2-6alkenyl or1-6-alkyloxy; in particular hydrogen, halogen, C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxy or1-6-alkyloxy;

when p is equal to 1, then R7represents aryl-C1-6-alkyl or hydroxy;

Z represents a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-7), (8) and (9);

R10or R11choose, each independently, from hydrogen; halogen; hydroxyl; amino; C1-6-alkyl; nitro; polyhalogen-C1-6-alkyl; cyano; cyano-C1-6-alkyl; tetrazolo-C1-6-alkyl; aryl; heteroaryl; heteroaryl-C1-6-alkyl; aryl(hydroxy)-C1-6-alkyl; arylcarbamoyl; C1-6-alkylcarboxylic; C3-7-cycloalkylcarbonyl; C3-7-cycloalkyl(hydroxy)-C1-6-alkyl; aryl-C1-6-and what Biloxi-C 1-6-alkyl; C1-6-alkyloxy-C1-6-alkyloxy-C1-6-alkyl; C1-6-alkylcarboxylic-C1-6-alkyl; C1-6-allyloxycarbonyl-C1-6-alkyloxy-C1-6-alkyl; hydroxy-C1-6-alkyloxy-C1-6-alkyl; C1-6-allyloxycarbonyl-C2-6-alkenyl; C1-6-alkyloxy-C1-6-alkyl; C1-6-allyloxycarbonyl; aminocarbonyl; hydroxy-C1-6-alkyl; amino-C1-6-alkyl; hydroxycarbonyl; hydroxycarbonyl-C1-6-alkyl, and -(CH2)v-(C(=O))r-(CHR19)u-NR13R14;

v is 0 or 1;

u is 0 or 1;

R12represents hydrogen or C1-6-alkyl;

R13and R14choose, each independently, from hydrogen; C1-12-alkyl; C1-6-alkylcarboxylic; C1-6-alkylsulfonyl; aryl-C1-6-alkylcarboxylic; C3-7-cycloalkylcarbonyl; -(CH2)k-NR15R16;1-12of alkyl, substituted Deputy selected from hydroxy, hydroxycarbonyl, cyano, C1-6-allyloxycarbonyl or aryl; or

R13and R14together with the nitrogen atom to which they are attached, form morpholinyl, pyrrolidinyl, piperazinil or piperazinil, substituted Deputy, selected from C1-6-alkyl or aryl-C1-6-allyloxycarbonyl;

k = 2;

R15and R16choose the, each independently, from hydrogen, C1-12-alkyl or aryl-C1-6-allyloxycarbonyl; in particular hydrogen, C1-6-alkyl or aryl-C1-6-allyloxycarbonyl; or

R15and R16together with the nitrogen atom to which they are attached, form morpholinyl, piperazinil or piperazinil, substituted C1-6-allyloxycarbonyl;

aryl represents phenyl or phenyl substituted by halogen; and

heteroaryl represents pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl, oxadiazolyl or tetrazolyl may be optionally substituted by one Deputy, selected from C1-6-alkyl, aryl or aryl-C1-6-alkyl.

The seventh group of preferred compounds (hereinafter called the group "G7") consists of those compounds of formula (I), in which

m is 0; n is 1 or 2, in particular 1; p is 0; s is 0; t is 0; X represents CH2;represents-CR9=C<, and R9represents hydrogen or C1-6-alkyl, preferably hydrogen or methyl, more preferably hydrogen, or R9together with one of R2or R20forms a direct bond; R1represents hydrogen; R3represents hydrogen; and R6represents hydrogen.

The eighth group of more than pre the reverent compounds (hereinafter called the group "G8") consists of those compounds of formula (I) or compounds of group "G7", the definition of which is given above, in which

R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, hydroxy-C1-6-alkyl, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxy, amino, C2-6alkenyl or1-6-alkyloxy; in particular hydrogen, halogen, C1-6-alkyl, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxy, amino or1-6-alkyloxy;

more preferably R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, hydroxy-C1-6-alkyl, polyhalogen-C1-6-alkyl, hydroxy, amino, C2-6alkenyl or1-6-alkyloxy; in particular hydrogen, halogen, C1-6-alkyl, polyhalogen-C1-6-alkyl, hydroxy, amino or1-6-alkyloxy;

even more preferably R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, hydroxyl-C1-6-alkyl, hydroxyl, C2-6alkenyl or1-6-alkyloxy; in particular hydrogen, halogen, C1-6-alkyl, hydroxy or1-6-alkyloxy;

most preferably, R4and R5represent, each independently, hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6alkenyl or1-6-alkyloxy (as, for example, R4and R5may present with the fight, each independently hydrogen, methyl or metiloksi).

The ninth group of more preferred compounds (hereinafter called the group "G9") consists of those compounds of formula (I) or compounds of any of the groups G7 or G8, which are defined above, in which

Z represents a radical selected from (a-1), (a-2), (a-3), (a-4) and (a-5);

or preferably Z represents a radical selected from (a-1), (a-2) and (a-4).

The tenth group of more preferred compounds (hereinafter called the group "G10") consists of those compounds of formula (I) or compounds of any of the groups "G7", "G8" or "G9", which are defined above, in which

R10or R11choose, each independently, from hydrogen, halogen, hydroxy, amino, C1-6-alkyl, nitro, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, tetrazol-C1-6of alkyl, aryl, heteroaryl, heteroaryl-C1-6of alkyl, aryl(hydroxy)-C1-6-alkyl, arylcarbamoyl,1-6-alkylsulphonyl,3-7-cycloalkylcarbonyl,3-7-cycloalkyl(hydroxy)-C1-6-alkyl, aryl-C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyloxy-C1-6-alkyl, C1-6-alkylcarboxylic-C1-6-alkyl, C1-6-allyloxycarbonyl-C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyloxy-C1-6-alkyl, C1-6 -allyloxycarbonyl-C2-6-alkenyl,1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl, aminocarbonyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, hydroxycarbonyl, hydroxycarbonyl-C1-6-alkyl, and -(CH2)v-(C(=O))r-(CHR19)u-NR13R14;

v is 0 or 1;

r is 0 or 1;

u is 0 or 1;

R13and R14choose, each independently, from hydrogen; C1-12-alkyl; C1-6-alkylcarboxylic; C1-6-alkylsulfonyl; aryl-C1-6-alkylcarboxylic; C3-7-cycloalkylcarbonyl; -(CH2)k-NR15R16;1-12of alkyl, substituted Deputy selected from hydroxy, hydroxycarbonyl, cyano, C1-6-allyloxycarbonyl or aryl; or

R13and R14together with the nitrogen atom to which they are attached, form morpholinyl, pyrrolidinyl, piperazinil or piperazinil, substituted Deputy, selected from C1-6-alkyl or aryl-C1-6-allyloxycarbonyl;

k = 2;

R15and R16choose, each independently, from hydrogen; C1-12-alkyl or aryl-C1-6-allyloxycarbonyl; in particular hydrogen, C1-6-alkyl or aryl-C1-6-allyloxycarbonyl; or

R15and R16together with the nitrogen atom to which they are attached, form morpholinyl, piperazinil or PI is erzini, replaced With1-6-allyloxycarbonyl;

R12represents hydrogen or C1-6-alkyl.

The eleventh group of more preferred compounds (hereinafter called the group "G11") consists of those compounds of group "G10", as defined above, in which

R10or R11choose, each independently, from hydrogen, hydroxy, amino, C1-6-alkyl, nitro, polyhalogen-C1-6-alkyl, cyano, aryl, aryl-C1-6of alkyl, aryl(hydroxy)-C1-6-alkyl, arylcarbamoyl,1-6-alkyloxy,1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl, aminocarbonyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, hydroxycarbonyl and -(CH2)v-(C(=O))r-(CH2)u-NR13R14;

v is 0 or 1;

r is 0 or 1;

u = 0;

R13and R14choose, each independently, from hydrogen, C1-6-alkyl, -(CH2)k-NR15R16and C1-12of alkyl, substituted hydroxy; or

R13and R14together with the nitrogen atom to which they are attached, form pyrrolidinyl;

k = 2;

R15and R16represent, each independently, With1-6-alkyl;

R12represents hydrogen or C1-6-alkyl, preferably hydrogen.

The twelfth group of more preferred compounds (the alley called the group "G12") consists of those compounds of group "G10", the definition of which is given above, in which

R10and R11choose, each independently, from hydrogen, hydroxy, hydroxy-C1-6-alkyl; and R12represents hydrogen or C1-6-alkyl, preferably hydrogen (as, for example, R10and R11can be selected, each independently, from hydrogen, hydroxy and hydroxymethyl; and R12can represent hydrogen or methyl, preferably hydrogen).

The thirteenth group of more preferred compounds (hereinafter called the group "G13") consists of those compounds of formula (I) or compounds of any of the groups "G7", "G8", "G9", "G10", "G11 or G12", which are defined above, in which

aryl represents phenyl or phenyl substituted by halogen; and

heteroaryl represents pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl, oxadiazolyl or tetrazolyl may be optionally substituted by one Deputy, selected from C1-6the alkyl, aryl and aryl-C1-6-alkyl.

The fourteenth group of more preferred compounds (hereinafter called the group "G14") consists of those compounds of group "G13", as defined above, in which

aryl represents phenyl or phenyl substituted by halogen; and

heteroaryl represents pyridinyl or indolyl.

Fifteenth the group is particularly preferred compounds (hereinafter called the group "G15") consists of those compounds of formula (I) or any subgroup, in which

m is 0; n is 1 or 2, in particular 1; p is 0; s is 0; t is 0; X represents CH2;represents-CR9=C<, and R9represents hydrogen or C1-6-alkyl, more preferably hydrogen, or R9together with one of R2or R20forms a direct bond; R1represents hydrogen; R3represents hydrogen; R4and R5represent, each independently, hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6alkenyl or1-6-alkyloxy; in particular hydrogen, C1-6-alkyl or C1-6-alkyloxy; R6represents hydrogen; Z is a radical selected from (a-1), (a-2) and (a-4); and R10or R11represents, each independently, hydrogen, hydroxy or hydroxy-C1-6-alkyl.

Sixteenth group of especially preferred compounds (hereinafter called the group "G16") consists of those compounds of formula (I) or any subgroup in which

m is 0; n is 1 or 2, in particular 1; p is 0; s is 0; t is 0; X represents CH2;represents-CR9=C<, and R9represents hydrogen or methyl, or R9together with one of R2or R20forms a direct bond; R1is dored; R3represents hydrogen; R4and R5represent, each independently, hydrogen, methyl or metiloksi; R6represents hydrogen; Z is a radical selected from (a-1), (a-2) and (a-4); and R10or R11represents, each independently, hydrogen, hydroxy or hydroxymethyl.

Seventeenth group of especially preferred compounds (hereinafter called the group "G17") consists of those compounds of formula (I) or, whenever possible, any of their subgroups, which are defined above, in which

represents-CR9=C<, and then the dotted line represents a bond, -C(=O)-CH<, -CHR9-CH< or-CHR9-N<, where each R9represents independently hydrogen or C1-6-alkyl, or where R9together with one of R2or R20forms a direct connection; in particular,represents-CR9=C<, and then the dotted line represents a bond, -CHR9-CH< or-CHR9-N<, where each R9represents independently hydrogen or C1-6-alkyl, or where R9together with one of R2or R20forms a direct link; in a more particular case ofrepresents-CR9=C<, and then the dotted line represents a bond, where the each R 9represents independently hydrogen or C1-6-alkyl, or where R9together with one of R2or R20forms a direct connection.

Preferably in compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", the substituents in the Central phenyl cycle other than R2and R20may be in the para(p-)-position.

In the embodiment, when m is equal to 1 when the substituents in the Central phenyl cycle other than R2and R20are metaprogram when s is 0 and t is equal to 0, then Z can represent a radical selected from (a-1), (a-3), (a-4), (a-5), (6), (7) or (a-8).

In the preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17" (repeat any of the above groups "G1"-"G17"used in this description covers specific reference to any or each connection group "G1", "G2", "G3", "G4", "G5", "G6", "G7", "G8", "G9", "G10", "G11", "G12", "G13", "G14", "G15", "G16" or "G17", which are defined in this specification), R2and R20choose, each independently, from halogen, cyano, amino, mono - or di(C1-6-alkyl)amino, C1-6of alkyl, aryl, heteroaryl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, hydroxy-C1-6-alkyl, polyhalogen-C1-6-alkyl, preferably Pergale is-C 1-6-alkyl, C1-6-alkyloxy, polyhalogen-C1-6-alkyloxy, preferably peralagan-C1-6-alkyloxy, aryl-C1-6-alkyloxy, heteroaryl-C1-6-alkyloxy,1-6-alkylthio, aaltio, preferably phenylthio,1-6-alkylsulphonyl, hydroxy-C1-6-alkylsulphonyl,1-6-allyloxycarbonyl,1-6-alkylcarboxylic,1-6-alkylcarboxylic, morpholinyl, piperidinyl, pyrrolidinyl and piperazinil; or R2and R20together with the Central phenyl cycle form naphthalenyl.

In another preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20choose, each independently, from C1-6of alkyl, aryl, heteroaryl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, hydroxy-C1-6-alkyl, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkyloxy,1-6-alkyloxy, aryl-C1-6-alkyloxy, heteroaryl-C1-6-alkyloxy,1-6-alkylthio, aaltio, preferably phenylthio,1-6-alkylsulphonyl, hydroxy-C1-6-alkylsulphonyl,1-6-allyloxycarbonyl,1-6-alkylcarboxylic,1-6-alkylcarboxylic, morpholinyl, piperidinyl, pyrrolidinyl and piperazinil, and any of these groups optionally and independently replaced the Jena one or more, preferably one or two, substituents selected from halogen, hydroxy, cyano, amino, mono - or di(C1-6-alkyl)amino, C1-6-alkyl, polyhalogen-C1-6of alkyl, aryl, heteroaryl and C1-6-alkyloxy; or R2and R20together with the Central phenyl cycle form naphthalenyl.

In a particularly preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20choose, each independently, from halogen, cyano, C1-6-alkyl, hydroxy-C1-6-alkyl, polyhalogen-C1-6-alkyl, preferably peralagan-C1-6-alkyl, C1-6-alkyloxy,1-6-alkylcarboxylic and morpholinyl; or R2and R20together with the Central phenyl cycle form naphthalenyl.

In another preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20choose, each independently, from halogen, C1-6-alkyl, polyhalogen-C1-6-alkyl, preferably peralagan-C1-6-alkyl, and C1-6-alkyloxy, or R2and R20together with the Central phenyl cycle form naphthalenyl.

In another preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17 is, R2and R20choose, each independently, from halogen, C1-6-alkyl and C1-6-alkyloxy.

In another preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20choose, each independently, from halogen, C1-6-alkyl, C1-6-alkyloxy, hydroxy-C1-6-alkyl, or R2and R20together with the Central phenyl cycle form naphthalenyl.

In another particularly preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20choose, each independently from fluorine, chlorine, bromine, cyano, methyl, hydroxymethyl, trihalomethyl, preferably trifloromethyl, metiloksi, methylcobalamine and morpholinyl, or R2and R20together with the Central phenyl cycle form naphthalenyl.

In another preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20choose, each independently from fluorine, chlorine, methyl, trifloromethyl, metiloksi, or R2and R20together with the Central phenyl cycle form naphthalenyl.

In another preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above g is UPP "G1"-"G17", R2and R20choose, each independently from fluorine, chlorine, methyl, metiloksi.

In another preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20choose, each independently from fluorine, chlorine, bromine, methyl, metiloksi, hydroxymethyl, or R2and R20together with the Central phenyl cycle form naphthalenyl.

In another preferred embodiment of the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20choose, each independently, from halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl,1-6-alkyloxy, hydroxyl-C1-6-alkyl, -NR21R22where R21represents hydrogen and R22represents a C1-6-alkylsulphonyl; or R2and R20together with the phenyl cycle to which they are attached, form naphthalenyloxy group, or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct connection; in particular, R2and R20choose, each independently, from chlorine, fluorine, bromine, cyano, trifloromethyl, methyl, morpholinyl, metiloksi, hydroxymethyl, -NH-C(=O)-CH3; or R2and R20together with the phenyl cycle, to the which they are attached, form naphthalenyloxy group, or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct connection.

Some preferred and yet non-restrictive embodiments of compounds of formula (I), in particular compounds of any of the above groups "G1"-"G17", include compounds, combinations of substituents R2and R20in which are given in table 1.

Table 1
CombinationR2R20
1With1-6-alkylWith1-6-alkyl
2methylmethyl
3peralagan-C1-6-alkylperalagan-C1-6-alkyl
4trifluoromethyltrifluoromethyl
5halogenWith1-6-alkyl
6chlorine methyl
7halogenhalogen
8fluoridefluoride
9chlorinechlorine
10halogenWith1-6-alkyloxy
11fluoridemetiloksi
12halogenWith1-6-alkylcarboxylic
13fluorideacetylamino
14halogenhydroxy-C1-6-alkyl
15brominehydroxymethyl
16cyanomorpholinyl
17R2and R20together with the Central phenyl cycle form naphthalenyl

In one embodiment particularly interesting combination is R 2and R20include combinations of№№ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 17, shown in table 1, in particular combinations№№ 2, 4, 6, 8, 9, 11 and 17, shown in table 1.

In another embodiment particularly interesting combination of R2and R20include combinations of№№ 5, 6, 7, 8, 9, 10 and 11 listed in table 1, in particular the combination of No. 10 and 11 listed in table 1.

In another embodiment particularly interesting combination of R2and R20include combinations of№№ 1, 2, 5, 6, 7, 8, 9, 10, 11, 14, 15 and 17, shown in table 1, in particular the combination of No. 10 and 11 listed in table 1.

Thus, examples of the preferred groups of compounds consists of those compounds of formula (I) or any subgroup in which

m is 0; n is 1 or 2; p is 0; s is 0; t is 0; X represents CH2;represents-CR9=C<, and R9represents hydrogen or C1-6-alkyl, more preferably hydrogen; R1represents hydrogen; R3represents hydrogen; R4and R5represent, each independently, hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6alkenyl or1-6-alkyloxy; R6represents hydrogen; Z is a radical selected from (a-1), (a-2) and (a-4); R10or R11represents, each independently, hydrogen, is hydroxy or hydroxy-C 1-6-alkyl; R12represents hydrogen or C1-6-alkyl, preferably hydrogen; and

R2and R20choose, each independently, from halogen, cyano, C1-6-alkyl, hydroxy-C1-6-alkyl, polyhalogen-C1-6-alkyl, preferably peralagan-C1-6-alkyl, C1-6-alkyloxy,1-6-alkylcarboxylic and morpholinyl; or R2and R20together with the Central phenyl cycle form naphthalenyl; or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct link;

more preferably R2and R20choose, each independently, from halogen, C1-6-alkyl, polyhalogen-C1-6-alkyl, preferably peralagan-C1-6-alkyl, and C1-6-alkyloxy, or R2and R20together with the Central phenyl cycle form naphthalenyl;

also more preferably, R2and R20you can choose, each independently, from halogen, C1-6-alkyl and C1-6-alkyloxy;

and more preferably R2and R20you can choose, each independently, from halogen, C1-6-alkyl, C1-6-alkyloxy, hydroxy-C1-6-alkyl, or R2and R20together with the Central phenyl cycle form naphthalenyl;

even more preferably R2and R20 choose, each independently from fluorine, chlorine, bromine, cyano, methyl, hydroxymethyl, trihalomethyl, preferably trifloromethyl, metiloksi, methylcobalamine and morpholinyl; or R2and R20together with the Central phenyl cycle form naphthalenyl; or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct link;

even more preferably R2and R20choose, each independently from fluorine, chlorine, methyl, trifloromethyl, metiloksi, or R2and R20together with the Central phenyl cycle form naphthalenyl;

also more preferably, R2and R20choose, each independently from fluorine, chlorine, methyl, metiloksi;

and more preferably R2and R20choose, each independently from fluorine, chlorine, bromine, methyl, metiloksi, hydroxymethyl, or R2and R20together with the Central phenyl cycle form naphthalenyl;

and also especially preferably, R2and R20can have the values listed in table 1.

Another embodiment comprises compounds of formula (I)

their N-oxide forms, salts of accession, solvate or a stereochemical isomeric forms, where

m is 0, 1 or 2, and when m is 0, this then implies direct from the IDE;

n is 0, 1, 2 or 3, and when n is 0 then implies a direct link;

p is 0 or 1, and when p is 0, this then implies a direct link;

s is 0 or 1 and when s is 0, this then implies a direct link;

t is 0 or 1, and when t is 0, this then implies a direct link;

X represents C(=O) or CHR8where

R8selected from hydrogen, C1-6-alkyl, C3-7-cycloalkyl, -C(=O)-NR17R18, carboxyl, aryl-C1-6-allyloxycarbonyl, heteroaryl, heteroarylboronic, heteroaryl-C1-6-allyloxycarbonyl, piperazinylcarbonyl, pyrrolidinyl, piperidinylcarbonyl,1-6-allyloxycarbonyl,1-6of alkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl,3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl, piperazinylcarbonyl, substituted Deputy selected from hydroxy, hydroxy-C1-6-alkyl, hydroxy-C1-6-alkyloxy-C1-6-alkyl, pyrrolidinyl, substituted hydroxy-C1-6-alkyl, and piperidinylcarbonyl substituted by one or two substituents selected from hydroxy, C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl(dihydroxy)-C1-6-alkyl and C1-6-alkyloxy(hydroxy)-sub> 1-6-alkyl;

R17and R18choose, each independently, from hydrogen, C1-6-alkyl, di(C1-6-alkyl)amino-C1-6-alkyl, aryl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, hydroxy-C1-6-alkyl(C1-6-alkyl) or hydroxy-C1-6-alkyl(aryl-C1-6-alkyl);

represents-CR9=C<, and then the dotted line represents a bond, -C(=O)-CH<, -C(=O)-N<, -CHR9-CH< or-CHR9-N<, where each R9represents independently hydrogen or C1-6-alkyl, or where R9together with one of R2or R20forms a direct link;

R1represents hydrogen, aryl, heteroaryl,1-6-allyloxycarbonyl,1-12-alkyl or C1-12-alkyl, substituted by one or two substituents selected independently from hydroxy, aryl, heteroaryl, amino, C1-6-alkyloxy, mono - or di(C1-6-alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil,1-6-alkylpiperazine, aryl-C1-6-alkylpiperazine, heteroaryl-C1-6-alkylpiperazine,3-7-cycloalkylcarbonyl and C3-7-cycloalkyl-C1-6-alkylpiperazine;

R2and R20choose, each independently, from

of halogen, hydroxy, cyano, nitro, carboxyl;

polygalov the h 1-6-alkyl, peralagan-C1-6-alkyl, polyhalogen-C1-6-alkyloxy, peralagan-C1-6-alkyloxy;

With1-6-alkyl, C3-7-cycloalkyl,2-6-alkenyl, aryl, heteroaryl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-7-cycloalkyl-C1-6-alkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil,1-6-alkyloxy, aryloxy, heteroaromatic,1-6-alkylthio, aaltio, heteroaromatic,1-6-alkylsulphonyl,3-7-cycloalkylcarbonyl, arylcarbamoyl, heteroarylboronic,1-6-allyloxycarbonyl,3-7-cycloalkylcarbonyl, aryloxyalkyl, heteroarylboronic,1-6-alkylcarboxylic,3-7-cycloalkylcarbonyl, arylcarboxylic or heteroarylboronic, and any of these groups optionally and independently substituted by one or more, preferably one or two, substituents selected from halogen, hydroxy, cyano, nitro, carboxyl, amino, mono - or di(C1-6-alkyl)amino, C1-6-alkyl, polyhalogen-C1-6of alkyl, aryl, heteroaryl,1-6-alkyloxy,1-6-alkylsulphonyl,1-6-allyloxycarbonyl and C1-6-alkylcarboxylic; and

-(CH2)w-(C(=O))yNR21R22where

w is equal to 0, 1, 2, 3, 4, 5 or 6, and when w is equal to 0, then implies direct the ligature;

y is 0 or 1, and when y is 0, this then implies a direct link;

R21and R22choose, each independently, from hydrogen, C1-6-alkyl, C3-7-cycloalkyl,1-6-alkylcarboxylic and aryl-C1-6-alkylsulphonyl, and any of these groups optionally and independently substituted by one or more, preferably one or two, substituents selected from halogen, hydroxy, amino, mono - or di(C1-6-alkyl)amino, C1-6-alkyl, polyhalogen-C1-6-alkyl, C1-6-alkyloxy, aryl and heteroaryl,

or R21and R22together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl or piperazinil, and any of these groups optionally and independently substituted by one or more, preferably one or two, substituents selected from C1-6-alkyl, polyhalogen-C1-6-alkyl, C1-6-alkyloxy,3-7-cycloalkyl,3-7-cycloalkyl-C1-6-alkyl, aryl-C1-6-alkyl and heteroaryl-C1-6-alkyl;

or R2and R20together with the phenyl cycle to which they are attached, form naphthalenyloxy group, optionally substituted by one or more, preferably one or two, substituents selected from halogen, hydroxy, amino, mono - or di(C1-6and the keel)amino, With1-6-alkyl, polyhalogen-C1-6-alkyl, C1-6-alkyloxy, aryl and heteroaryl;

or R2and R20together form a bivalent radical of the formula -(CH2)b-where b is equal to 3, 4 or 5, optionally substituted by one or more, preferably one or two, substituents selected from halogen, hydroxy, amino, mono - or di(C1-6-alkyl)amino, C1-6-alkyl, polyhalogen-C1-6-alkyl, C1-6-alkyloxy, aryl and heteroaryl;

or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct link;

R3represents hydrogen, C1-6-alkyl, heteroaryl,3-7-cycloalkyl,1-6-alkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl or3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and heteroaryl;

R4and R5represent, each independently, hydrogen, halogen, C1-6-alkyl, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, hydroxy, amino or1-6-alkyloxy, or

R4and R5together form a bivalent radical selected from methylenedioxy or Ethylenedioxy;

R6represents hydrogen, C1-6-allyloxycarbonyl or1-6-alkyl;

when the R is equal to 1, then R7represents hydrogen, aryl-C1-6-alkyl, hydroxy or heteroaryl-C1-6-alkyl;

Z represents a radical selected from the

where

R10or R11choose, each independently, from hydrogen, halogen, hydroxy, amino, C1-6-alkyl, nitro, polyhalogen-C1-6-alkyl, cyano, cyano-C1-6-alkyl, tetrazol-C1-6of alkyl, aryl, heteroaryl, aryl-C1-6-alkyl, heteroaryl-C1-6of alkyl, aryl(hydroxy)-C1-6-alkyl, heteroaryl(hydroxy)-C1-6-alkyl, arylcarbamoyl, heteroarylboronic,1-6-alkylsulphonyl, aryl-C1-6-alkylsulphonyl, heteroaryl-C1-6-alkylsulphonyl,1-6-alkyloxy,3-7-cycloalkylcarbonyl,3-7-cycloalkyl(hydroxy)-C1-6-alkyl, aryl-C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyloxy-C1-6-alkyl, C1-6-alkylcarboxylic-C1-6-alkyl, C1-6-allyloxycarbonyl-C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl-C2-6-alkenyl,1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl,1-6-alkylcarboxylic, aminocarbonyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, hydroxy what arbonia, hydroxycarbonyl-C1-6-alkyl, and -(CH2)v-(C(=O))r-(CHR19)u-NR13R14where

v is equal to 0, 1, 2, 3, 4, 5 or 6, and when v is 0, this then implies a direct link;

r is 0 or 1, and when r is 0, this then implies a direct link;

u = 0, 1, 2, 3, 4, 5 or 6, and when u is equal to 0, this then implies a direct link;

R19represents hydrogen or C1-6-alkyl;

R13and R14choose, each independently, from hydrogen, C1-12-alkyl, C1-6-alkylsulphonyl,1-6-alkylsulfonyl, aryl-C1-6-alkylsulphonyl,3-7-cycloalkyl,3-7-cycloalkylcarbonyl, -(CH2)k-NR15R16With1-12of alkyl, substituted Deputy selected from hydroxy, hydroxycarbonyl, cyano, C1-6-allyloxycarbonyl,1-6-alkyloxy, aryl or heteroaryl or3-7-cycloalkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl, amino, aryl-C1-6-alkyl, heteroaryl or heteroaryl-C1-6-alkyl, or

R13and R14together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl, piperazinil or piperazinil, substituted Deputy, selected from C1-6-alkyl, aryl-C1-6-alkyl, aryl-C1-6-allyloxycarbonyl, heteroaryl-C1-6of alkyl, With3-7-cycloalkyl and C3-7-cycloalkyl-C1-6-alkyl; where

k is equal to 0, 1, 2, 3, 4, 5 or 6, and when k is 0, this then implies a direct link;

R15and R16choose, each independently, from hydrogen, C1-6-alkyl, aryl-C1-6-allyloxycarbonyl,3-7-cycloalkyl,1-12of alkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl and heteroaryl, and C3-7-cycloalkyl, substituted Deputy selected from hydroxy, C1-6-alkyloxy, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl, or

R15and R16together with the nitrogen atom to which they are attached, form morpholinyl, piperazinil or piperazinil, substituted C1-6-allyloxycarbonyl;

R12represents hydrogen, C1-6-alkyl, C3-7-cycloalkyl,1-6-alkyl, substituted Deputy selected from hydroxy, amino, C1-6-alkyloxy and aryl, or C3-7-cycloalkyl, substituted Deputy selected from hydroxy, amino, aryl and C1-6-alkyloxy;

aryl represents phenyl or naphthalenyl;

each phenyl or naphthalenyl may be optionally substituted by one, two or three substituents selected each independently from halogen, hydroxy, C1-6-alkyl, amino, polyhalogen-C1-6-alkyl and C1-6 -alkyloxy; and

each phenyl or naphthalenyl may be optionally substituted bivalent radical selected from methylenedioxy, Ethylenedioxy;

heteroaryl represents pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;

each pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl may be optionally substituted by one, two or three substituents selected each independently from halogen, hydroxy, C1-6-alkyl, amino, polyhalogen-C1-6of alkyl, aryl, aryl-C1-6-alkyl or C1-6-alkyloxy; and

each pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl may be optionally substituted bivalent radical selected from methylenedioxy, Ethylenedioxy.

Another embodiment is especially preferred compounds consists of those compounds of formula (I), in which s is 0; t is 0; m is 0; p is 0; n is 1 or 2; R1represents hydrogen; R2and R20choose, each independently, from halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl,1-6-alkyloxy, hydroxy-C1-6-alkyl, -NR21R22where R21isone hydrogen and R 22represents a C1-6-alkylsulphonyl; or R2and R20together with the phenyl cycle to which they are attached, form naphthalenyloxy group, or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct bond; R3represents hydrogen; R4and R5represent, each independently, hydrogen, C1-6-alkyl, C1-6-alkyloxy, hydroxy-C1-6-alkyl, C2-6alkenyl; R6represents hydrogen;represents-CR9=C<, and then the dotted line represents a bond; R9represents hydrogen or C1-6-alkyl; X represents CH2; Z represents a radical selected from (a-1), (a-2) or (a-4); R10and R11choose, each independently, from hydrogen, hydroxy or hydroxy-C1-6-alkyl.

It should be borne in mind that when in the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", R2and R20together with the phenyl cycle to which they are attached, form naphthalenyloxy group, optionally substituted as specified above, then Deputy

and

may be associated with one and the same cycle or different is diversified cycles specified naphthalenyloxy group.

In the preferred embodiment R2and R20together with the phenyl cycle to which they are attached, may form naphthalenyloxy group, which can be represented by the formulas (II-a) and (II-b), more preferably formula (II-a):

where the substituents have the meanings specified above.

In another embodiment in compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", one of R2or R20matter referred to in this description previously, and the other of R2or R20together with R9forms a direct connection. Connection as an example of compounds of formula (I), whererepresents-CR9=C< and in which R20together with R9forms a direct link can be drawn in the General formula (III):

where the substituents have the meanings specified above.

Preferably when one of R2or R20together with R9forms a direct connection, indicated a direct link can be a link with the Central carbon atom of the phenyl cycle, neighboring (i.e., in o-position to the Central carbon atom of the phenyl cycle, which is linked to a group -(CH2)m-.

As you can imagine, in the compounds of formula (I), and in particular with the dinnieh any of the above groups "G1"-"G17", the substituents R2and R20can be in the ortho(o-)-, meta(m-)- or para(p-)-positions relative to each other in the Central phenyl cycle.

When R2and R20together form a bivalent radical of the formula -(CH2)b-where b is equal to 3, 4 or 5, optionally substituted as specified above, then the connection specified bivalent radical preferably attached to the Central phenyl cycle in ortho(o-)position relative to each other.

As you can imagine, in the compounds of formula (I), and in particular in compounds of any of the above groups "G1"-"G17", four Deputy at the Central phenyl cycle can be in different positions relative to each other. For example, and without limitation, compounds in which the substituents at the Central phenyl cycle other than R2and R20are in the para-position, i.e. the 1-, 4-, the substituents R2and R20can be in positions 2 and 3, or in positions 2 and 5, or in positions 2 and 6 and so on

Table 2 provides a list of preferred, non-limiting examples of compounds of formula (I)obtained according to the present invention. In the table the following abbreviations are used: .HCl denotes a salt of hydrochloric acid, TPL denotes the melting temperature.

In one embodiment particularly preferred are compounds№№ 2, 5, 6, 10, 12, 17, 25, 29, 30, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 and 49, even more preferred connection№№ 5, 6, 10, 17, 29, 30, 31, 34, 35, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 and 49 and even more preferred compounds№№ 5, 39, 41, 42, 43 and 47; such compounds may show particularly pronounced desired biological action.

In another embodiment particularly preferred are compounds№№ 7, 9, 17, 29, 30, 31, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and 49, even more preferably the compound No. 42; such compounds may show particularly pronounced desired biological action.

In another embodiment particularly preferred are compounds№№ 2, 6, 8, 10, 11, 12, 13, 15, 17, 18, 19, 22, 29, 30, 31, 32, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 51, 52 and 53, even more preferred connection№№ 38, 39, 42, 44, 45, 46 and 47; such compounds may show particularly pronounced desired biological effect.

In another embodiment particularly preferred are the following compounds:

including any stereochemical isomeric form;

their N-oxide forms, their salts joining or solvate.

In another embodiment particularly preferred are compounds№№ 39, 41, 42, 47, 49 and 63.

The compounds of formula (I), their N-oxides, pharmaceutically acceptable salt, solvate and their stereochemical isomeric form can be obtained in the usual way. The initial substance and some intermediate compounds are known compounds and are commercially available, or can be obtained according to conventional reaction procedures generally known in the technique.

A number of these ways to get will be described later in detail. Other ways to obtain the final compounds of formula (I) described in the examples.

The compounds of formula (I) can be obtained by the interaction of the intermediate compounds of formula (IV) with an intermediate compound of formula (V)in which W represents a suitable removable group, such as, for example, halogen, for example fluorine, chlorine, bromine or iodine, or Radik the l sulfonyloxy, such as methylsulfonylamino, 4-methylphenylsulfonyl etc. Interaction can be performed in a solvent inert to the reaction, such as, for example, alcohol such as methanol, ethanol, 2-methoxyethanol, propanol, butanol and the like; a simple ether, e.g. 1,4-dioxane, a solution of chloritoid in 1,4-dioxane, 1,1'-oxybisethane and the like; a ketone, e.g. 4-methyl-2-pentanone; or N,N-dimethylformamide, nitrobenzene, acetonitrile, acetic acid, etc. or mixtures thereof. The addition of an appropriate base, such as, for example, a carbonate of alkali or alkaline earth metal, or organic carbonate, or organic bases such as triethylamine, or sodium carbonate, or N,N-diisopropylethylamine, can be used to neutralize the acid which is liberated during the reaction. A small amount of the corresponding metal iodide such as sodium iodide or potassium, can be added for promotion of the reaction. Mixing can increase the reaction rate. The interaction can be conveniently carried out at a temperature ranging from room temperature to the temperature of education phlegmy the reaction mixture and, if desired, the reaction can be performed at high pressure.

The compounds of formula (I)in which X represents CH called in this description of the compounds of formula (I-a), can be obtained by the interaction of the compounds of formula (I)in which X represents C(=O), referred to in this description of the compounds of formula (I-b), with lithium aluminum hydride or NR3in a suitable solvent, such as tetrahydrofuran.

The compounds of formula (I-a) can also be obtained by interaction of the corresponding carboxaldehyde formula (VI) with an intermediate compound of formula (VII) in the presence of an appropriate reagent such as sodium borohydride, such as tetrahydroborate sodium or centripetality applied to the polymer in a suitable solvent, such as alcohol, for example methanol.

In the same way, the compounds of formula (I)in which t is equal to 1, referred to in this description of the compounds of formula (I-C), can be obtained by the interaction of the intermediate compounds of formula (IV) with an appropriate carboxaldehyde of formula HC(=O)Z.

The compounds of formula (I), in which s is equal to 1, referred to in this description of the compounds of formula (I-d), can be obtained by the interaction of the intermediate compounds of formula (VIII) with lithium aluminum hydride in a suitable RA is the solvent, such as tetrahydrofuran.

The compounds of formula (I)in which R4represents-CH2HE called in the description of the compounds of formula (I-e), can be obtained by the interaction of the intermediate compounds of formula (XXIV) with lithium aluminum hydride in a suitable solvent, such as tetrahydrofuran.

The compounds of formula (III) can be obtained by conversion of the intermediate compounds of formula (XIX) in the presence of a strong acid, such as HCl, in a suitable solvent, such as tetrahydrofuran.

The compounds of formula (III), in which s is 0 and R3represents hydrogen, referred to in this description of the compounds of the formula (III-a), can be obtained by the interaction of the intermediate compounds of formula (IV), in which s is 0, R3represents hydrogen,represents-CR9=C< and R9together with R20forms a direct connection, referred to in this description of the intermediate compounds of the formula (IV-C), with an intermediate compound of formula (V)in which W represents an appropriate delete a group that has the values specified above, in a solvent inert to the reaction, such as, for example, sleep is t, for example, methanol, ethanol, 2-methoxyethanol, propanol, butanol and the like; a simple ether, e.g. 1,4-dioxane, 1,1'-oxybisethane and the like; a ketone, e.g. 4-methyl-2-pentanone; or N,N-dimethylformamide, nitrobenzene, acetonitrile, acetic acid, etc. the Addition of an appropriate base, such as, for example, a carbonate of alkali or alkaline earth metal, or an organic carbonate, or organic base such as triethylamine or sodium carbonate, can be used to neutralize the acid which is liberated during the reaction.

The compounds of formula (III)in which R6represents hydrogen, referred to in this description of the compounds of the formula (III-b), can also be obtained by reaction of Fischer (synthesis of indoles), on the basis of the intermediate compounds of formula (XXII) and (XXIII).

The compounds of formula (I) and their intermediate compounds also can be transformed into each other by reactions known in the art, or conversion of functional groups. Some of these transformations have already been described above. Other examples are the hydrolysis of esters of carboxylic acids to the corresponding carboxylic acids or alcohols; hydrolysis of amides to the corresponding carboxylic acids or amines; hydrolysis of NITR the crystals to the corresponding amides; the amino group of the imidazole or phenyl can be substituted for the hydrogen known in the art by reaction of diazotization and subsequent replacement of diazogroup hydrogen; alcohols can be converted into esters and ethers; primary amines can be converted into secondary or tertiary amines; the double bond can be gidrirovanii to the corresponding simple relations; iodine radical the phenyl group can be converted into ester group by the introduction of carbon monoxide in the presence of a suitable palladium catalyst; and so on

Intermediate compounds of formula (IV)in which X represents CH2, m is 0, s is 0 and R3represents hydrogen, referred to in this description of the intermediate compounds of the formula (IV-a), can be obtained by reduction of nitro group to amino, proceeding from the intermediate compounds of formula (IX)in the presence of a suitable catalyst, such as Raney Nickel or palladium-on-charcoal, and an appropriate reductant, such as hydrogen, in a suitable solvent, such as methanol, ethanol, toluene, tetrahydrofuran or mixtures thereof. In the case of compounds containing groups that are sensitive to catalytic hydrogenation, can be used Pt/C, optional poisoned by thiophene. You can use the V2O5as an auxiliary catalyst. Appropriate what rastvoritelyami for this reaction are tetrahydrofuran or toluene.

Intermediate compounds of formula (IV)in which X represents C(=O), s 0 and R3represents hydrogen, referred to in this description of the intermediate compounds of the formula (IV-b), can be obtained by the interaction of the intermediate compounds of formula (X) with an intermediate compound of formula (XI) in the presence of an appropriate reagent combinations, such as monohydrochloride N'-(ethylcarbodiimide)-N,N-dimethyl-1,3-propandiamine (EDC) and 1-hydroxy-1H-benzotriazole (NOVT). The interaction can be performed in the presence of a base, such as triethylamine, in a suitable solvent such as a mixture of dichloromethane and tetrahydrofuran.

Intermediate compounds of formula (VI) can be obtained by the interaction of the intermediate compounds of formula (XII) with lithium aluminum hydride in a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formula (VIII) can be obtained by the interaction of the intermediate compounds of formula (XIII) with an intermediate compound of formula (XIV) in the presence of iodide, 2-chloro-1-methylpyridine and triethylamine in a suitable solvent, such as acetonitrile.

Intermediate compounds of formula (IX) can be obtained by the interaction of the intermediate compounds of formula (XV) with an intermediate compound of formula (XVI)in which a represents a suitable removable group, such as, for example, halogen, for example fluorine, chlorine, bromine or iodine, or With1-6-alkyloxy, for example, metiloksi, in a suitable solvent, such as dimethylsulfoxide or toluene, preferably in the presence of a base, such as NaHCO3or N,N-diisopropylethylamine optionally at elevated temperatures, for example at about 60°C.

Intermediate compounds of formula (XIII), in which R20represents-CH2HE called in this description of the intermediate compounds of formula (XVI-a), can be obtained by recovering the intermediate compounds of formula (XXV) with a suitable reducing agent such as NaBH4, in a suitable solvent, such as alcohol, for example methanol.

Intermediate compounds of formula (XIII) can be obtained by conversion of the intermediate of formula (XVII) in the presence of sodium hydroxide and water in a suitable solvent, such as ethanol.

Intermediate compounds of formula (XVII) is to teach the interaction of the intermediate compounds of formula (XVIII), in which a represents a suitable removable group that has the values listed above, with an intermediate compound of formula (XV) in a suitable solvent, such as diisopropylethylamine.

Intermediate compounds of formula (XV)in which R1represents hydrogen, referred to in this description of the intermediate compounds of formula (XV-a), can be obtained by reaction of the intermediate of formula (XXVI) in the presence of a suitable catalyst, such as Raney Nickel, ammonia and a suitable solvent, such as alcohol, for example methanol.

Intermediate compounds of formula (XXVI) can be obtained by the interaction of the intermediate compounds of formula (XXVII), which is a suitable counterion, such as, for example, iodide with sodium cyanide in a suitable solvent such as N,N-dimethylformamide.

Intermediate compounds of formula (XXVI)in which R4or R5represents a hydroxy-C1-6-alkyl (for example, -CH(CH3)-Or-C(CH3)2-HE), can be obtained from the corresponding aldehyde or ketone (e.g.,- C(=O)H or-C(=O)-CH3) interaction with methylmagnesium in a suitable solvent, such as Tetra drofuran.

Intermediate compounds of formula (XXVI)in which R4or R5represents-C(=O)-CH3can be obtained from the corresponding compounds-CH(CH3)-HE interaction with a suitable oxidant, such as reagent dessa-Martin.

Intermediate compounds of formula (XXVII) can be obtained from the corresponding secondary amine interaction with a suitable alkylating agent, such as methyliodide, in a suitable solvent, such as alcohol, for example ethanol.

Intermediate compounds of formula (IV-C) can be obtained by reduction of nitro group to amino, proceeding from the intermediate compounds of formula (XX)in the presence of a metal catalyst, such as Raney Nickel, and an appropriate reductant, such as hydrogen, in a suitable solvent, such as methanol or ethanol.

Intermediate compounds of formula (XX) can be obtained from intermediates of formula (XXI), in which D represents the corresponding remove galactography, such as, for example, bromine or iodine, by reaction Hake cyclic compounds in the presence of a base, such as, for example, MgO, and palladianism catalyst, such as Pd(OAc)2, in a suitable inert reaction solvent such as an alcohol, for example methanol, acetonitrile is whether DMF.

Intermediate compounds of formula (XIX) or (XXIV) can be obtained according to the interaction described above to obtain compounds of formula (I) from intermediates of formula (IV) and (V).

Some compounds of formula (I) and some intermediate compounds can have in their structure at least one stereogenic center. Any such stereogenic center may be present independently in the R - or S-configuration.

Some compounds of formula (I) and some intermediate compounds of the present invention may contain an asymmetric carbon atom. Such compounds, as obtained by the procedures described earlier in this description, may, as a rule, represent a racemic mixture of enantiomers or diastereoisomers, which can be separated from each other, following known in the art procedures cleavage. For example, diastereoisomer can be divided by physical methods such as selective crystallization or chromatography methods, for example, countercurrent chromatography, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures, turning first mentioned racemic mixture using suitable disintegrating agents, such as, for example, chiral acids, see the si diastereomeric salts or compounds, and then separating these mixtures of diastereomeric salts or compounds, for example, selective crystallization, supercritical fluid chromatography, or using chromatography such as liquid chromatography and the like methods; and finally converting these separated diastereomeric salts or compounds into the corresponding enantiomers. Stereochemical pure isomeric forms may also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds, provided that what is happening stereospecific reactions occur.

The compounds of formula (I), their pharmaceutically acceptable salts accession acids or bases, N-oxides and stereoisomeric forms possess valuable pharmacological properties in that they inhibit the interaction between p53 and MDM2.

The term "MDM2" (murine double minor 2 (Murine Double Minute 2)) is used in this description to refer to the protein, resulting from expression of the mdm2 gene. As part of its values specified, the term "MDM2" encompasses all proteins encoded by mdm2, their mutants, their alternative slice-proteins and their phosphorylated proteins. In addition, as used in this description, the term "MDM2" includes analogs of MDM2, for example MDMX (also known as MDM4, and homologues MDM2 and counterparts from other animals, such as the er, the human homologue of HDM2 or human analogue of HDMX.

The terms "inhibition of interaction" or "inhibitor interaction"as used in this description to denote prevent or reduce direct or indirect Association of one or more molecules, peptides, proteins, enzymes or receptors; or preventing or weakening of the normal activity of one or more molecules, peptides, proteins, enzymes or receptors.

The term "inhibitor of the interaction between p53 and MDM2" or "inhibitor of p53-MDM2" is used in this description to describe an agent that increases the expression of p53 in the analysis described in C.1. This increase may be caused by, but without limitation, one or more of the following mechanisms of action:

- inhibition of the interaction between p53 and MDM2,

direct Association with MDM2 or p53 protein,

interaction with upper or lower targets, such as kinases, or by the activities of the enzymes involved in ubiquitination or modification SUMO,

- sequestration or transfer of MDM2 and p53 in different cell compartments

- modulation of proteins associated with MDM2, for example (but without limitation) P63, R, E2F-1, Rb, p21waf1 cip1 or, HIF1-alpha, Foxo3A, p14ARF,

negative modulation or interference in the expression of MDM2 and/or activity of MDM2, for example (but without limitation) the impact on its cellular localization, post-translational modification of nuclear export, activity ubiquitinate or interference in the binding of MDM2 with the proteasome, modulation of the interaction between MDM2-proteasome,

- direct or indirect stabilization of p53 protein, such as holding it in its functional structural form or by preventing erroneous installation,

- increased expression of p53 protein or the expression of members of the p53 family, such as P63 and R,

- increased p53 activity, for example (but without limitation) the strengthening of its transcriptional activity, and/or

- increased expression of genes and proteins path signaling p53, for example (but without limitation) p21waf1, cip1, MIC-1 (GDF-15), PIG-3, Bax, Puma, Noxa and ATF-3.

Therefore, the present invention discloses compounds of formula (I) for use as pharmaceuticals, in particular for the treatment of cancer or related diseases, for the inhibition of tumor growth, inhibition of the interaction between MDM2 and p53, to modulate the interaction of MDM2-proteasome.

In addition, the invention also relates to the use of compounds to obtain drugs for the treatment of disorders mediated by the interaction of the p53-MDM2, where the specified compound is a compound of formula (I).

The term "treatment"as used herein, covers any treatment of a disease and/or condition in an animal, particularly a human, and includes: (i) the warning of the occurrence of the disease and/or condition in the subject, which may be predisposed to the disease and/or condition, but which it is not yet diagnosed as available; (ii) suppression of the disease and/or condition, i.e. stop its development; (iii) the weakening of the disease and/or condition, i.e., the induction of regression of the disease and/or condition.

The term "a disorder mediated by the interaction of the p53-MDM2" refers to any unwanted or harmful condition which is a result of the interaction between the MDM2 protein and p53 or other cellular proteins that induce apoptosis, induce the death of cells or regulate the cell cycle.

This invention also relates to a method of treatment of disorders mediated by the interaction of the p53-MDM2, through the introduction of an effective amount of the compounds of the present invention to a subject, e.g. a mammal (and more preferably a human)in need of such treatment.

Compounds according to the invention may have antiproliferative effects in tumor cells, even if these cells are devoid of functional p53. In the more particular case of the compounds according to the invention can possess antiproliferative action on tumors with wild type p53 or mutant p53 and/or tumors, sverkhekspressiya MDM2.

Thus, this invention also relates to a method of inhibiting ROS is and tumors by introducing an effective amount of the compounds of the present invention to a subject, for example, a mammal (and more preferably a human)in need of such treatment.

Examples of tumors, including malignancy in adults and children, which can inhibit the compounds of the present invention, include, but are not limited to, lung cancer, including small cell lung cancer and non-small cell lung cancer (e.g. adenocarcinoma), pancreatic cancer, cancer of the colon (e.g. colorectal carcinomas, such as, for example, adenocarcinoma of colon cancer and adenoma colon cancer), esophageal cancer, oral squamous cell carcinoma, carcinoma of the tongue, gastric carcinoma, liver cancer, nasopharynx cancer, tumors of the hematopoietic system lymph origin (e.g., acute lymphocytic leukemia In-cell lymphoma, Burkitt's lymphoma), nahodkinskuju lymphoma (e.g., lymphoma cells, tissues, clothing sporangium), Hodgkin's disease, myeloid leukemias (for example, acute myeloid leukemia (AML) or chronic myeloid leukemia (CML), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), follicular thyroid cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin, soft tissue sarcoma, liposarcoma, gastrointestinal stromal sarcoma, a malignant tumor of the sheaths perifericos the x nerves (MPNST), sarcoma Ewing's sarcoma, leiomyosarcoma, mesenchyme chondrosarcoma, lymphosarcoma, fibrosarcoma, rhabdomyosarcoma, melanoma, teratocarcinoma, neuroblastoma, brain tumors, gliomas, benign tumor of the skin (for example, keratoacanthoma), carcinoma of the breast (for example, launched breast cancer, carcinoma of the kidney, ovarian carcinoma, cervical carcinoma, endometrial carcinoma, carcinoma of the bladder, prostate cancer including the advanced disease and hormonerefractory prostate cancer, testicular cancer, osteosarcoma, head and neck cancer, epidermal carcinoma, multiple myeloma (e.g., refractory multiple myeloma), mesothelioma. Specific cancers that can be treated by the compounds of the present invention, are breast cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia (AML).

Compounds of the present invention can also be used for the treatment and prevention of inflammatory conditions.

Thus, this invention also relates to a method of treating and preventing inflammatory conditions through the introduction of an effective amount of the compounds of the present invention to a subject, e.g. a mammal (and more preferably human), n is gaudemus in such treatment.

Compounds of the present invention can also be used to treat autoimmune diseases and conditions. The term "autoimmune disease" refers to any disease in which the immune system of the animal react hostile to the native antigen. The term "self antigen" refers to any antigen that is commonly found in the animal body. Typical autoimmune diseases include, but are not limited to, Hashimoto's thyroiditis, graves ' disease, multiple sclerosis, pernicious anemia, Addison disease, insulin-dependent diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus), dermatomyositis, Crohn's disease, Wegener's granulomatosis, antiglomerular disease of the basal membrane, antiphospholipid syndrome, dermatitis herpetiformis 25, allergic encephalomyelitis, glomerulonephritis, membranous glomerulonephritis syndrome?, myasthenic syndrome Lambert-Eaton heavy pseudoparalysis myasthenia, bullous pemphigoid, polyendocrinopathy, disease, Reiter syndrome stiff person.

Thus, this invention also relates to a method of treatment of autoimmune diseases and conditions through the introduction of an effective amount of the compounds of the present invention to a subject, for example the EP to a mammal (and more preferably human), in need of such treatment.

Compounds of the present invention can also be used to treat diseases associated with conformationally unstable or improperly folded proteins.

Examples of diseases associated with conformationally unstable or improperly folded proteins include, but are not limited to, cystic fibrosis (CFTR), Marfan syndrome (fibrillin), amyotrophic lateral sclerosis (superoxide dismutase), scurvy (collagen), a disease of maple syrup (the complex of alpha-ketoacid dehydrogenase), imperfect osteogenesis (procollagen Pro-alpha type I), a disease of Creutzfeldt-Jakob disease (prion), Alzheimer's disease (beta-amyloid), familial amyloidosis (secrete lysozyme), cataract (crystalline), family hypercholesterinemia (LDL-receptor)the deficiency of l-antitrypsin, disease, and Tay-Sachs (beta hexosaminidase), retinitis pigmentosa (rhodopsin) and leprechaunism (insulin receptor).

Thus, this invention also relates to a method for treatment of diseases associated with conformationally unstable or improperly folded proteins through the introduction of an effective amount of the compounds of the present invention to a subject, e.g. a mammal (and more preferably a human)in need of such treatment.

Taking into account their useful pharmaceutical the fir properties of the discussed compounds can be included in various pharmaceutical forms for administration.

In order to obtain the compositions of this invention, an effective amount of the compounds of the present invention as an active ingredient unite with careful mixing with a pharmaceutically acceptable carrier, which may take a variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a single dosage form, preferably suitable for administration orally, rectally, transdermally, or parenterally by injection. For example, upon receipt of the compositions in oral dosage form, you can use any of the usual pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, substances that contribute to the scattering, and the like, in the case of powders, pills, capsules and tablets.

Because of the ease of introduction of tablets and capsules represent the most advantageous oral unit dosage forms, using, obviously, the solid pharmaceutical carriers. For parenteral compositions, the carrier will usually include sterile water, at least more than the parts, although there may be other ingredients, for example, facilitate solubility. For example, you can get solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. You can also get a suspension for injection in this case, you can use the appropriate liquid carriers, suspendresume agents and similar substances. In the compositions suitable for percutaneous administration, the carrier optionally comprises an agent that enhances penetration and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which does not have a significant harmful impact on the skin. These supplements can facilitate the introduction into the skin and/or can help in obtaining the desired compositions. These compositions can be administered in a number of ways, for example in the form of a transdermal patch, in the form of droplets, in the form of ointment.

Particularly advantageous to obtain the above pharmaceutical composition in unit dosage form for ease of administration and uniformity of dosage. Used in this description and the claims, the term "unit dosage form" refers to physically discrete units suitable as single doses, presentada unit contains a preset amount of the active ingredient, designed to obtain the desired therapeutic effect, in Association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including tablets scored or coated), capsules, pills, sachet powders, tablets, solutions or suspensions for injection, teaspoons, tablespoons, etc. and their separated sets.

The connection according to the invention is administered in amounts effective to inhibit the interaction between MDM2 and p53 or other cellular protein that induces apoptosis, induces cell death regulates the cell cycle and regulates migration, or invasion, or metastasis of tumor cells, in particular in a quantity sufficient to modulate the interaction of MDM2-proteasome.

Oncogenic potential of MDM2 is determined not only by its ability to suppress p53, but also its ability to regulate other proteins of the tumor suppressors, such as retinoblastoma protein pRb and theseassociations the transcription factor E2F1, P63, R.

Thus, the connection of the present invention is administered in an amount effective to modulate the interaction between MDM2 and transcription factor E2F1.

Specialists in the art can easily determine the effective amount from the test results presented in this description later. Ka is the rule, it is assumed that therapeutically effective amount will be from 0.005 mg/kg to 100 mg/kg body weight and in particular from 0.005 mg/kg to 10 mg/kg of body weight. It might correspond to the introduction of the required dose as a single dose, two, three, four or more subds through appropriate intervals during the day. These subdata can be obtained in the form of a unit dosage forms, for example, containing from 0.5 to 500 mg, in particular from 1 mg to 500 mg, typical from 10 mg to 500 mg of the active ingredient at a standard dosage form.

Depending on the method of administration of the pharmaceutical composition will preferably contain from 0.05 to 99 wt.%, more preferably from 0.1 to 70 wt.%, even more preferably from 0.1 to 50 wt.% compounds of the present invention, from 1 to 99.95 wt.%, more preferably from 30 to 99.9 wt.%, even more preferably from 50 to 99.9 wt.% pharmaceutically acceptable carrier, all percentages are given relative to the total weight of the composition.

In another aspect, the present invention relates to a combination of an inhibitor of p53-MDM2 with another anti-cancer, mainly for use in medicine, specifically in the treatment of cancer or related diseases.

To ensure the above conditions, the compounds according to the invention can advantageously be used socetanii with one or more other drugs, typical with other anticancer drugs or adjuvants in cancer therapy. Examples of anti-cancer tools or adjuvant (maintenance therapy) include, but are not limited to:

- coordination of the platinum compounds such as cisplatin, optionally, in combination with amifostine, carboplatin or oxaliplatin;

connection taxane, such as paclitaxel, particles of paclitaxel associated protein (abraxane™), or docetaxel;

inhibitors of topoisomerase I, such as compound camptothecin, such as irinotecan, SN-38, topotecan, topotecan hydrochloride;

inhibitors of topoisomerase II, such as antitumor epipodophyllotoxin or derivatives podofillotoksina, such as etoposide, etoposide phosphate or teniposide;

- antineoplastic vinylchloride, for example vinblastine, vincristine or vinorelbine;

- antitumor derivatives of nucleosides such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hydrochloride, capecitabine, cladribine, fludarabine, nelarabine;

- alkylating agents such as nitrogen mustard gas analogue or nitrosoanatabine, for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustin, altretamine, busulfan, dacarbazine, estramustine, ifosfamide, optionally, in combination with mesna, PIP is Broman, procarbazine, streptozocin, temozolomide, uracil;

- antitumor anthracycline derivatives for example daunorubicin, doxorubicin, optionally, in combination with dexrazoxane, doxil, idarubitsin, mitoxantrone, epirubicin, epirubicin hydrochloride, valrubicin;

- molecules that target the IGF-1 receptors, such as microrotation;

derivatives of tetracaine, such as tetracetic;

- glucocorticoids, such as prednisone;

- antibodies, such as trastuzumab (anti-HER2), rituximab (anti CD20), gemtuzumab, ozogamicin gemtuzumab, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;

antagonists of estrogen receptors, or selective estrogen receptor modulators or inhibitors of the synthesis of estrogens, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;

- aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozole;

tools that promote differentiation, such as retinoids, vitamin D, or the means of blocking the metabolism of retinoic acid (RAMBA)for example accutane;

inhibitors of DNA methyltransferase, for example azacytidine or decitabine;

- antifolates, such as premetrexed disodium;

- antibiotics, the example of actinomycin D, bleomycin, mitomycin C, dactinomycin, karminomitsin, daunomycin, levamisole, plicamycin, mithramycin;

the antimetabolites, such as Clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacytidine, cytarabine, floxuridine, pentostatin, tioguanin;

tools, inducing apoptosis, and antiangiogenic agents such as inhibitors of Bck-2, for example YC 137, BH 312, ABT 737, hossipole, HA 14-1, TW 37 or cekanova acid;

- topulinovatiei tools, such as complestatin, colchicine or nocodazole;

inhibitors of kinases (e.g., inhibitors of EGFR (epithelial growth factor receptor), MTKI (inhibitors of multi-kinase)inhibitors mTOP), for example flavopiridol, of imatinib mesilate, erlotinib, gefitinib, dasatinib, lapatinib, ditosylate of lapatinib, sorafenib, sunitinib, maleate of sunitinib, temsirolimus;

inhibitors farnesyltransferase, such as tipifarnib;

inhibitors discontiuation (HDAC), such as sodium butyrate, suberoylanilide acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin And, vorinostat;

inhibitors path ubiquitin-proteasome, such as PS-341, MLN.41 or bortezomib;

- yondelis;

- inhibitors of telomerase, such as teamstation;

- inhibitors of matrix metalloproteinases, such as batimastat, marimastat, prinostit or metastat;

recombinant interleukins, n is the sample aldeslakin, denileukin diftitox, interferon-alpha 2A, interferon-alpha 2b, peginterferon-alpha 2b;

inhibitors MARC;

- retinoids, such as alitretinoin, bexarotene, tretinoin;

- trioxide of arsenic;

- asparaginase;

- steroids, such as propionate dromostanolone, acetate megestrol, nandrolone (decanoate, phenpropionate), dexamethasone;

agonists or antagonists of gonadotropin-releasing hormone, for example abarelix, goserelin acetate, acetate histrelin, acetate leuprolide;

- thalidomide, lenalidomide;

- mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase;

- mimetics VN, for example ABT-737;

the MEK inhibitors, such as PD98059, AZD6244, CI-1040;

- analogues of colony-stimulating factors such as filgrastim, pegfilgrastim, sargramostim; erythropoietin or its analogs (e.g., darbepoietin-alpha; interleukin-11; oprelvekin; zoledronate, zoledronicaa acid; fentanyl; bisphosphonate; palifermin.

As indicated above, the compounds of the present invention also have therapeutic applications in the sensitization of tumor cells to radiotherapy and chemotherapy.

Therefore, the compounds of the present invention can be used as a "radiosensibility" and/or "chemosensitization or can be given in conjunction with any "radiosensitisation" and/or what chemosensitization".

The term "radiosensibility"used in this description, is defined as a molecule, preferably a molecule of low molecular weight, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and/or promotion of the treatment of diseases which are curable with ionizing radiation.

The term "chemosensitization"used in this description, is defined as a molecule, preferably a molecule of low molecular weight, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promotion of the treatment of diseases that are treatable chemotherapeutics.

In the literature proposed several mechanisms of action type of radio sensibilizators, including: hypoxic cell radio sensibilizators (for example, the compounds 2-intorimidazole and dioxides benzotriazine) mimic oxygen or, on the other hand, behave during hypoxia like biostimulatory; regionsince cellular radio sensibilizators (for example, halogenated pyrimidines) can be analogues of DNA bases and mainly implemented in the DNA molecule and/or to interfere with the normal mechanisms of DNA repair; and are assumed to be different is e other possible mechanisms of action of radio sensibilizators in the treatment of disease.

In many cancer treatment protocols currently used radio sensibilizators in combination with x-rays. Examples of radio sensibilizators activated x-ray radiation include, but are not limited to, the following: metronidazole, misonidazole, dexmethylphenidate, pilonidal, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromosuccinimide (BUdR), 5-iodetachdevice (IUdR), bromosuccinimide, ftordezoksiuridin (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of these substances.

Photodynamic therapy (PDT) of cancer uses visible light as radiant activator sensitizer. Examples of photodynamic radio sensibilizators include, but are not limited to, the following: hematoporphyrin derivatives, Photofrin, derivatives benzoporphyrin, Ethiopian tin, foobarred, bacteriochlorophyll-naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of these substances.

The radio sensibilizators you can type in combination with a therapeutically effective amount of one or more other compounds, including, but not limited to, compounds that promotirovat enable radio is sensibilization in target cells; compounds that regulate the flow of therapeutics, nutrients and/or oxygen to the target cells; chemotherapeutic agents that act on the tumor with additional irradiation with or without him; or other therapeutically effective compounds for treating cancer or other diseases.

Chemosensitization you can type in combination with a therapeutically effective amount of one or more other compounds, including, but not limited to, compounds that promotirovat enable chemosensitization in the target cells; compounds which control the flow of therapeutics, nutrients and/or oxygen to the target cells; chemotherapeutic agents that act on the tumor with additional irradiation or without it, or other therapeutically effective compounds for treating cancer or other disease. Found that calcium antagonists such as verapamil, are applicable in combination with antineoplastics means for establishing sensitivity to chemotherapy in tumor cells that are resistant to recognized chemotherapeutic means and for augmentation of the effectiveness of these compounds in zlokacestvennosti resistant to medicines.

Taking into account their useful pharmacological properties, the components of the coefficients of the combinations according to the invention, i.e. one or more other drugs and inhibitors of p53-MDM2 according to the present invention may be incorporated in various pharmaceutical forms for administration. Components can be introduced in separate pharmaceutical compositions or in a single pharmaceutical composition containing all components.

Therefore, the present invention also relates to pharmaceutical compositions comprising one or more other medicines and inhibitor of p53-MDM2 according to the present invention together with a pharmaceutical carrier.

The present invention also relates to the use of the combinations according to the invention when receiving a pharmaceutical composition for inhibiting the growth of tumor cells.

The present invention also relates to a product containing a first active ingredient is an inhibitor of p53-MDM2 according to the present invention and, as an additional active ingredient, one or more anti-cancer tools, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

One or more other medicines and inhibitor of p53-MDM2 according to the present invention can be administered simultaneously (e.g. in separate or single composition) or sequentially in any order. the latter case, two or more compounds will be introduced with the period and in the amount and in the manner sufficient to ensure that the achieved beneficial or synergistic effect. It should be borne in mind that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the input of certain other funds and inhibitor of p53-MDM2, their route of administration, the particular tumor, which is treated, and the specific recipient, which is treated. The optimal way and order of administration and dosage amounts and regimes can be easily identified by experts in the art using conventional methods and taking into account the information presented in this description.

The mass ratio of the compounds of the present invention and one or more other anti-cancer tools in combination can be determined by a person skilled in the art. This ratio and the exact dosage and frequency of injection depends on the particular compounds according to the invention and the other(them) cancer(s) funds(funds), a state from which it is treated, the severity of the condition, which are treated, age, weight, gender, diet, time of administration and General physical condition of a patient, the method of administration, and other drug therapies, which can make patients what NT which is well known to specialists in this field of technology. Moreover, it is clear that the effective daily amount may be reduced or increased depending on the response of a subject of which they treat, and/or depending on the evaluation of the physician who prescribes the compounds of the present invention. A certain mass ratio of the compounds of formula (I) and another anti-cancer agent may range from 1/10 to 10/1, typical from 1/5 to 5/1, even typical 1/3 to 3/1.

The coordination compound of platinum is advantageous to introduce at a dose of 1-500 mg per square meter (mg/m2) the surface area of the body, for example 50-400 mg/m2in particular in the case of cisplatin in a dosage of about 75 mg/m2and carboplatin about 300 mg/m2in the course of treatment.

Connection taxane profitable to enter at a dose of 50-400 mg per square meter (mg/m2) the surface area of the body, for example 75-200 mg/m2in particular in the case of paclitaxel in a dosage of about 175-250 mg/m2and docetaxel approximately 75-150 mg/m2in the course of treatment.

Connection camptothecin profitable to enter at a dosage of 0.1 to 400 mg per square meter (mg/m2) the surface area of the body, for example 1-300 mg/m2in particular in the case of irinotecan at a dose of about 100-350 mg/m2and topotecan approximately 1-2 mg/m2in the course of treatment.

Protivoopujolevy is the first derivative podofillotoksina profitable to enter the dosage of 30-300 mg per square meter (mg/m 2) the surface area of the body, for example 50-250 mg/m2in particular in the case of etoposide at a dose of about 35-100 mg/m2and teniposide about 50-250 mg/m2in the course of treatment.

Antitumor vinylchlorid profitable to enter in the dosage of 2 to 30 mg per square meter (mg/m2) the surface area of the body, in particular in the case of vinblastine at a dose of about 3-12 mg/m2and vincristine at a dose of 1-2 mg/m2and vinorelbine at a dose of about 10-30 mg/m2in the course of treatment.

Antitumor derivative of the nucleoside profitable to enter the dosage of 200-2500 mg per square meter (mg/m2) the surface area of the body, for example 700-1500 mg/m2in particular, in the case of 5-FU at a dosage of about 200-500 mg/m2in the case of gemcitabine at a dose of about 800-1200 mg/m2in the case involving capecitabine about 1000-2500 mg/m2in the course of treatment.

Alkylating agent, such as nitrogen mustard gas analogue or nitrosoanatabine, it is advantageous to introduce at a dose of 100-500 mg per square meter (mg/m2) the surface area of the body, for example 120-200 mg/m2in particular in the case of cyclophosphamide at a dose of about 100-500 mg/m2if hlorambuzila in a dosage of about 0.1-0.2 mg/m2in the case of carmustine at a dose of approximately 150-200 mg/m2in the case of lomustina in a dosage of about 100-150 mg/m in the course of treatment.

Antitumor derivative anthracycline profitable to enter the dosage of 10-75 mg per square meter (mg/m2) the surface area of the body, for example 15-60 mg/m2in particular in the case of doxorubicin in a dosage of about 40-75 mg/m2in the case of daunorubicin at a dosage of about 25-45 mg/m2in the case of idarubitsina at a dose of 10-15 mg/m2in the course of treatment.

Antiestrogenic tool is advantageous to introduce at a dose of 1-100 mg per day depending on specific tools and condition, which are treated. Tamoxifen advantageously be administered orally at a dose of 5-50 mg, preferably 10-20 mg twice daily, continuing treatment a period of time sufficient to achieve and maintain a therapeutic effect. Toremifene advantageously administered orally in a dosage of about 60 mg once daily, continuing treatment a period of time sufficient to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1 mg once a day. Droloxifene advantageously administered orally in a dosage of about 20-100 mg once a day. Raloxifene advantageously administered orally in a dosage of about 60 mg once a day. Exemestane advantageously administered orally in a dosage of about 25 mg once a day.

Antibodies profitable to enter at a dose of about 1-5 mg aquadratic meter (mg/m 2) the surface area of the body or as it is known in the technique in the case of differences. Trastuzumab is advantageous to introduce at a dose of 1-5 mg per square meter (mg/m2) the surface area of the body, in particular 2-4 mg/m2in the course of treatment.

These dosages can be entered, for example once, twice or more per course of treatment that can be repeated, for example, every 7, 14, 21 or 28 days.

The compounds of formula (I), their pharmaceutically acceptable salts and stereoisomeric forms can be a valuable diagnostic properties in the sense that they can be used for detection and identification of interaction of the p53-MDM2 in a biological sample, comprising detecting or measuring the formation of a complex between the labeled compound, and/or p53 and/or MDM2 and/or other molecules, peptides, proteins, enzymes or receptors.

In the methods of detection or identification of connections can be used, which state agents-labels, such as radioisotopes, enzymes, fluorescent substances, luminescent substances, etc. are Examples of radioisotopes include125I131I3H and14C. Enzymes are usually amenable to detection by conjugation of the corresponding substrate, which in turn catalyzes the reaction, detectable. Their examples include, for example, beta-galactosidase, beta-glucoside is zu, alkaline phosphatase, peroxidase and malate dehydrogenase, preferably horseradish peroxidase. Fluorescent substances include, for example, luminal derived lyuminola, luciferin, acorin and luciferase.

Biological samples can be defined as the tissue of the body or body fluids. Examples of body fluids are cerebrospinal fluid, blood, plasma, serum, urine, sputum, saliva, etc.

The following examples illustrate the present invention.

EXPERIMENTAL PART

The dal in the present description the term "DIPEA" denotes N-ethyl-N-(1-methylethyl)-2-propanamine, K2CO3" means potassium carbonate, "CH2Cl2" means dichloromethane, "CH3HE" refers to methanol, "MgSO4" refers to magnesium sulfate "NaHCO3" indicates the monosodium salt of carbonic acid, "DMSO" means dimethyl sulfoxide, "TPL" means melting point, "CH3CN" stands for acetonitrile, "EtOAc" means ethyl acetate, "DIPE" means diisopropyl ether, "DMF" means N,N-dimethylformamide, "THF" means tetrahydrofuran, "V2O5" denotes an oxide of vanadium, "NaBH4" indicates tetrahydroborate(-1) sodium, "NaCl" means sodium chloride, "EtOH" refers to ethanol, "NH4OH" refers to the ammonium hydroxide. Column chromatography on Sunfire about who appoints HPLC with reversed phase using speakers Sunfire™ stationary phase of silicon dioxide, associated with C-18, Waters Corp. (Milford, Massachusetts).

A. Obtaining intermediates

Example A1

a) Obtaining an intermediate compound 1

A mixture of 1,2,3-Cryptor-5-nitrobenzene (0,0037 mol), 1H-indol-3-ethanamine (0,0037 mol) and DIPEA (0,0189 mol) was stirred at 120°C for 18 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with a mixture of CH2Cl2/CH3IT (a little). The organic layer is separated, dried (MgSO4), filtered, the solvent is evaporated to dryness and obtain 1.3 g (>100%) of intermediate compound 1.

b) Receiving the intermediate 2

A mixture of intermediate compound 1 (0,0037 mol) and 10% Pd/C (0,13 g) in toluene (50 ml) hydronaut at room temperature for 3 days under atmospheric pressure and then filtered through celite. The filtrate is evaporated to dryness. The residue is dissolved in CH2Cl2. The organic layer is separated, dried (MgSO4), filtered, the solvent is evaporated to dryness and receive 1.2 g (>100%) of intermediate compound 2.

Example A2

a) Obtaining an intermediate compound 3

A mixture of 2-chloro-5-nitro-1,3-bis(trifluoromethyl)benzene (0.002 mol), 1H-indol-3-ethanamine (0,0024 mol) and NaHCO3(0,0026 mol) in DM is O (4 ml) was stirred at 100°C for 48 hours, then cooled to room temperature and poured into H2O. Precipitated precipitated substance is filtered off, washed djatlovym ether and dried, yielding 0,41 g (49%) of intermediate compound 3 (TPL 152°C).

b) Obtaining an intermediate compound 4

A mixture of intermediate compound 3 (0,0008 mol) and Raney Nickel (0.36 g) in CH3HE (10 ml) hydronaut at room temperature for 18 hours under atmospheric pressure and then filtered through celite. The filtrate is evaporated to dryness. The residue is dissolved in CH2Cl2. The organic layer is separated, dried (MgSO4), filtered, the solvent is evaporated to dryness and obtain 0.32 g (96%) of intermediate compound 4.

Example A3

a) Obtaining an intermediate compound 5A

A mixture of 1,3-dichloro-2-fluoro-5-nitrobenzene (0,0048 mol), 1H-indol-3-ethanamine (0,0048 mol) and NaHCO3(0,0057 mol) in DMSO (10 ml) was stirred at 60°C overnight and cooled to room temperature. Add a mixture of water with ice. The mixture is extracted with EtOAc. The organic layer is decanted, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue is crystallized from CH3CN/DIPE. Precipitated precipitated substance is filtered off and dried, yielding of 1.03 g (62%) of intermediate compound 5A (TPL 98°C).

b) Obtaining promezhutochnogo the compounds 6A

A mixture of intermediate compound 5A (0,0027 mol) and 5% Pt/C (0.1 g) in V2O5(0.01 g), 4% solution of thiophene in DIPE (0.1 ml) and THF (20 ml) hydronaut at room temperature for 18 hours under atmospheric pressure. The catalyst is removed by filtration. The filtrate is evaporated to dryness and the gain of 0.91 g (100%) of intermediate compound 6A.

C) Obtaining an intermediate compound 5b

A mixture of 1,3-dichloro-2-fluoro-5-nitrobenzene (0,0048 mol), 1H-indole-2-methyl-3-ethanamine (0,004 mol) and NaHCO3(0,0048 mol) in DMSO (10 ml) was stirred at 60°C overnight and cooled to room temperature. Add a mixture of water with ice. Precipitated precipitated substance is filtered off, washed with CH3CN, dried and gain of 0.48 g (28%) of intermediate compound 5b (TPL 147°C).

d) Obtaining an intermediate compound 6b

A mixture of intermediate compound 5b (0,0013 mol) and 5% Pt/C (0.05 g) in V2O5(0.005 g), 4% solution of thiophene in DIPE (0.05 ml) and THF (10 ml) hydronaut at room temperature for 18 hours under atmospheric pressure and then filtered. The filtrate is evaporated to dryness and the gain of 0.48 g (100%) of intermediate compound 6b.

e) Receiving the intermediate 5s

A mixture of 1,3-dichloro-2-fluoro-5-nitrobenzene (0,0048 mol), 1H-in the ol-6-methoxy-3-ethanamine (0,0048 mol) and NaHCO 3(0,0057 mol) in DMSO (10 ml) was stirred at 60°C overnight and cooled to room temperature. Add a mixture of water with ice. Precipitated precipitated substance is filtered off, washed with CH3CN and dried, the solvent is evaporated to dryness and receive 1.2 g (66%) of intermediate compound 5C (TPL 116°C).

f) Receiving the intermediate 6s

A mixture of intermediate compound 5C (0,0031 mol) and 5% Pt/C (0.12 g) in V2O5(0,012 g), 4% solution of thiophene in DIPE (0,12 ml) and THF (25 ml) hydronaut at room temperature for 18 hours under atmospheric pressure and then filtered through celite. The filtrate is evaporated to dryness and receive 1.2 g (100%) of intermediate compound 6C.

Example A4

a) Obtaining an intermediate compound 7a

A mixture of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0,0026 mol), 1H-indol-3-ethanamine (0,0026 mol) and NaHCO3(0,0032 mol) in DMSO (5 ml) was stirred at 60°C overnight and cooled to room temperature. Add a mixture of water with ice. Precipitated precipitated substance is filtered off, washed with CH3CN and dried, yielding 0.54 g (62%) of intermediate compound 7a (TPL 146°C).

b) Obtaining an intermediate compound 8A

A mixture of intermediate compound 7a (0,0012 mol) and 5% Pt/C (0,049 g) in V2O5 (0.005 g), 4% solution of thiophene in DIPE (0,049 ml) and THF (10 ml) hydronaut at room temperature for 18 hours under atmospheric pressure. The catalyst is removed by filtration. The filtrate is evaporated to dryness and obtain 0.36 g (100%) of intermediate compound 8A.

C) Obtaining an intermediate compound 7b

A mixture of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0,0026 mol), 1H-indole-7-methyl-3-ethanamine (0,0026 mol) and NaHCO3(0,0032 mol) in DMSO (5 ml) was stirred at 60°C overnight and cooled to room temperature. Add a mixture of water with ice. Precipitated precipitated substance is filtered off, washed with CH3CN, the solvent is evaporated to dryness and the gain of 0.53 g (58%) of intermediate compound 7b (TPL 171°C).

d) Receiving the intermediate 8b

A mixture of intermediate compound 7b (0,0014 mol) and 5% Pt/C (0.05 g) in V2O5(0.005 g), 4% solution of thiophene in DIPE (0.05 ml) and THF (15 ml) hydronaut at room temperature for 18 hours under atmospheric pressure and then filtered through celite. The filtrate is evaporated to dryness and receive 0,49 g (100%) of intermediate compound 8b.

Example A5

a) Obtaining an intermediate compound (9)

To a solution of 4-bromo-5-fluoro-2-nitrobenzaldehyde (0.02 mol) in CH3HE (50 ml) at 5°C. add part by part NaBH4 (0,024 mol). The mixture is stirred at room temperature for 2 hours. Add saturated aqueous solution of NaCl. The mixture is extracted with CH2Cl2. The organic layer is separated, dried (MgSO4), filtered, the solvent is evaporated to dryness and receive 5 g (100%) of intermediate compound (9).

b) Obtaining an intermediate compound 10

A mixture of intermediate 9 (0.01 mol), 1H-indol-3-ethanamine (0.01 mol) and NaHCO3(0.012 mol) in DMSO (25 ml) was stirred at 60°C overnight and then cooled to room temperature. Add a mixture of water with ice. Precipitated precipitated substance is filtered off, washed with CH3CN and dried, yielding 1.77 g (45%) of intermediate compound 10.

C) Obtaining an intermediate compound (11)

A mixture of intermediate compound 10 (0,0045 mol), 5% Pt/C (0.18 g) and V2O5(0.02 g) in a 4% solution of thiophene (of 0.18 ml) and THF (50 ml) hydronaut at room temperature for 48 hours under atmospheric pressure and then filtered through celite. The filtrate is evaporated to dryness and obtain 1.7 g (100%) of intermediate compound (11).

Example A6

a) Obtaining an intermediate compound 12

A mixture of 1-fluoro-2-methyl-4-nitrobenzene (0,0103 mol), 7-methyl-1H-indol-3-ethanamine (0,0103 mol) and DIPEA (0,0515 mol) var who're asked at 120°C for 18 hours, then cooled to room temperature, diluted with a mixture of CH2Cl2/CH3IT (a little) and washed with 10% aqueous solution of K2CO3. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (4.1 g) purified column chromatography on silica gel (eluent CH2Cl2/cyclohexane, 70:30; 15-35 μm). Pure fractions are collected, the solvent is evaporated to dryness and obtain 1.45 g (45%) of intermediate compound 12.

b) Obtaining an intermediate compound 13

A mixture of intermediate compound 12 (0,0045 mol) and 5% Pt/C (0.15 g) in toluene (40 ml) hydronaut at room temperature for 18 hours under a 3 bar pressure, then filtered. The filtrate is evaporated to dryness and earn 1.25 g (100%) of intermediate compound 13.

C) Obtaining an intermediate compound 14

A solution of intermediate compound 13 (0.04 mol), (7S)-4-chloro-6,7-dihydro-5H-cyclopent[b]pyridine-7-ol (0,0044 mol) and 4 M HCl/dioxane (2 ml) in a mixture of CH3CN/EtOH (150 ml) was stirred at 65°C. over the weekend. Add a 10% aqueous solution of K2CO3and EtOAc. The mixture is extracted. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated. The residue (23 g) purified column chromatography (eluent CH2Cl2/CH3HE/NH OH, 93/7/1). Pure fractions are collected and the solvent is evaporated. The residue (14.2 g, 85%) crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding 10.4 g (63%) of intermediate compound 14.

Example A7

a) Obtaining an intermediate compound 15

A mixture of 1-fluoro-2,3-dimethyl-4-nitrobenzene (of 0.003 mol), 1H-indol-3-ethanamine (0,0036 mol) and NaHCO3(to 0.0039 mol) in DMSO (4 ml) was stirred at 100°C for 3 days and then cooled to room temperature. Type H2O. Precipitated precipitated substance is filtered off, washed with EtOH, then diethyl ether and dried. Part of the obtained fractions are dried at 60°C for 18 hours in a vacuum and get 0,052 g of intermediate compound 15 (TPL 178°C).

b) Obtaining an intermediate compound 16

A mixture of intermediate 15 (0,0022 mol) and Raney Nickel (0.7 g) in a mixture of CH3HE/THF (90/10) (20 ml) hydronaut at room temperature for 3 hours under atmospheric pressure and then filtered through celite. The filtrate is evaporated to dryness. The residue is dissolved in diethyl ether. The organic layer is separated, dried (MgSO4), filtered, the solvent is evaporated to dryness and obtain 0.64 g (100%) of intermediate 16 (TPL 161°C).

Example A8

a) Obtaining an intermediate link is 17

A mixture of 6-fluoro-2-(4-morpholinyl)-3-nitrobenzonitrile (0.002 mol), 1H-indol-3-ethanamine (0.002 mol) and NaHCO3(0,0024 mol) in DMSO (5 ml) was stirred at 60°C overnight and cooled to room temperature. Add a mixture of water with ice. Precipitated precipitated substance is filtered off, washed with CH3CN and dried, yielding 0.64 g (82%) of intermediate compound 17 (TPL 205°C).

b) Obtaining an intermediate compound 18

A mixture of intermediate 17 (0,0015 mol) and 5% Pt/C (0.06 g) in V2O5(0.01 g), 4% solution of thiophene in DIPE (0.06 ml) and THF (15 ml) hydronaut at room temperature for 18 hours under atmospheric pressure. The catalyst is removed by filtration. The filtrate is evaporated to dryness and receive 0,61 g (100%) of intermediate compound 18.

Example A9

a) Obtaining an intermediate compound 19

A mixture of N-(4,5-debtor-2-nitrophenyl)ndimethylacetamide (0,0023 mol), 1H-indol-3-ethanamine (0,0023 mol) and NaHCO3(0,0028 mol) in DMSO (5 ml) was stirred at 60°C overnight and then cooled to room temperature. Add a mixture of water with ice. Precipitated precipitated substance is filtered off and dried, yielding 0.73 g (88%) of intermediate compound 19 (TPL 166°C).

b) Obtaining an intermediate compound 20

A mixture of intermediate 19 (0.002 mol) and Raney Nickel (0.8 g) in CH3HE (15 ml) hydronaut at room temperature for 4 hours under atmospheric pressure and then filtered through celite. The filtrate is evaporated to dryness. The residue is dissolved in CH2Cl2. The organic layer is separated, dried (MgSO4), filtered, the solvent is evaporated to dryness and the gain of 0.68 g (100%) of intermediate compound 20.

Example a10

a) Obtaining an intermediate compound 21

A mixture of 1,2-debtor-3-methoxy-4-nitrobenzene (0,0074 mol), 7-methoxy-1H-indol-3-ethanamine (0,0074 mol) and NaHCO3(0,0088 mol) in DMSO (15 ml) was stirred at 60°C overnight and then cooled to room temperature. Add a mixture of water with ice. Precipitated precipitated substance is filtered off, washed with CH3CN, dried and gain of 2.27 g (85%) of intermediate compound 21 (TPL 164°C).

b) Obtaining an intermediate compound 22

A mixture of intermediate 21 (0,0058 mol), 5% Pt/C (0.21 g) and V2O5(0,021 g) in a 4% solution of thiophene in DIPE (of 0.21 ml) and THF (30 ml) hydronaut at room temperature for 48 hours under atmospheric pressure and then filtered through celite. The filtrate is evaporated to dryness and obtain 2.1 g (100%) of intermediate compound 22.

Example A11

Intermediate with the organisations, which include the other(s) Deputy(s) on 1H-indol-3-ilen cycle, can be obtained similarly to the above interactions using differently substituted 1H-indol-3-ethanamine, such as 2-methyl-1H-indol-3-ethanamine, 7-methyl-1H-indol-3-ethanamine, 6-methoxy-1H-indol-3-ethanamine or 7-methoxy-1H-indol-3-ethanamine.

Example A12

a) Obtaining intermediate compounds 23

A mixture of 1-methoxy-4-nitronaphthalene (of 0.0005 mol) and 1H-indol-3-ethanamine (of 0.0005 mol) in EtOH (3 ml) was stirred at 100°C for 18 hours and then evaporated to dryness. The residue (0.4 g) purified column chromatography on silica gel (eluent CH2Cl2, 100). Pure fractions are collected, the solvent is evaporated and get 0.03 g (10%) of intermediate 23 (TPL 211°C).

b) Obtaining intermediate compounds 24

A mixture of intermediate 23 (0.002 mol) and Raney Nickel (0.7 g) in EtOH (50 ml) hydronaut at room temperature for 18 hours under a 3 bar pressure, then filtered. The filtrate is evaporated to dryness. The residue (0.6 g) purified column chromatography on a kromasil (kromasil) (eluent CH2Cl2/CH3OH/NH4OH, 99/1/0,1 to 97/3/0,3; 5 μm). Pure fractions are collected, the solvent is evaporated and obtain 0.32 g (53%) of the intermediate compound 24 (TPL 148°C).

Example A13

a) Obtaining intermediate compounds 25

To a solution of methyl ester 3-[(dimethylamino)methyl]-1H-indole-7-carboxylic acid (0,0215 mol) in EtOH (50 ml) is added dropwise methyliodide (0,0215 mol). The mixture is stirred at room temperature for 24 hours. Precipitated precipitated substance is filtered off and washed with EtOH and obtain 7.5 g of the intermediate compound 25.

The product obtained is used directly in the next reaction stage.

b) Obtaining an intermediate compound 26

A mixture of intermediate 25 (0.02 mol) and sodium cyanide (0,026 mol) in DMF (75 ml) was stirred at 100°C for 2 hours. Add the water. Precipitated precipitated substance is filtered off and obtain 2.2 g of the intermediate compound 26.

The product obtained is used directly in the next reaction stage.

C) Obtaining an intermediate compound 27

To a solution of intermediate 26 and ammonia (7 M, 25 ml) under nitrogen atmosphere add Raney Nickel. The mixture hydronaut at a pressure of 3 bar at room temperature for 5 hours. The crude mixture is filtered through celite, the solvent is evaporated and obtain 2.2 g of the intermediate compound 27.

d) Obtaining an intermediate compound 28

A mixture of intermediate 27 (0,00504 mol), 2,3-debtor-6-nitroanisole (0,00504 mol) and sodium bicarbonate (0,00605 mol) in DMSO (110 ml) and heat at 60°C over night. The mixture is cooled to room temperature, then add the mixture of water with ice, the precipitated precipitated substance is filtered off, washed with CH3CN, dried and receive 0,860 g of intermediate compound 28.

e) Obtaining an intermediate compound 29

A mixture of intermediate 28 (0,0022 mol) and Raney Nickel (0,0147 mol) in CH3HE (25 ml) hydronaut at room temperature under atmospheric pressure H2during the weekend. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue is dissolved in CH2Cl2, the organic layer is dried over MgSO4, filtered, evaporated to dryness and obtain 0.6 g of the intermediate compound 29.

The product obtained is used directly in the next reaction stage.

f) Obtaining an intermediate compound 30

Get a mixture of intermediate 29 (0,00168 mol), 4-chloro-6,7-dihydro-5H-cyclopent[b]pyridine-7-ol (0,00168 mol) and 4 M solution of hydrogen chloride in dioxane (0,000336 mol) in a solution of CH3CN/EtOH (25 ml). The mixture was stirred at 65°C over night. Add a 10% aqueous solution of K2CO3, organicheskikh extracted with CH 2Cl2, dried (MgSO4), filtered and the solvent evaporated. The residue (0.9 g) purified column chromatography on silica gel (eluent CH2Cl2/CH3OH/NH4OH, gradient, 97/3/0,5; 90 g 15-40 μm). Pure fractions are collected and the solvent is evaporated. The residue is crystallized from CH3OH and get 0,160 g of intermediate compound 30.

Example A14

a) Obtaining an intermediate compound 31

3-[{Dimethylamino)methyl]-1H-indole-7-carboxaldehyde (0.13 mol) and jodean (0.14 mol) in EtOH (300 ml) was stirred at room temperature for 2 days. Precipitated precipitated substance is filtered off and dried, yielding 47 g of intermediate compound 31.

b) Obtaining an intermediate compound 32

Intermediate compound 31 (136,5 mmol) and sodium cyanide (177,5 mmol) in DMF (400 ml) was stirred at room temperature for 2 hours. Water is added and the reaction mixture extracted with EtOAc. The organic layer is separated, dried over MgSO4, filtered and evaporated. The residue is purified by high-performance liquid chromatography (heterogeneous SiOH 20-45 μm, 1000 g MATREX/mobile phase: 70% cyclohexane, 30% EtOAc). Pure fractions are collected, the solvent is evaporated and get to 11.8 g of intermediate compound 32.

C) Obtaining an intermediate compound 33

To a solution of intermediate 32 (0,022 mol) in THF (50 ml) is added dropwise methylmagnesium (0.07 mol). Add a 10% aqueous solution of NH4Cl and EtOAc. The reaction mixture was extracted and the organic layer is separated, dried over MgSO4, filtered and evaporated. The residue (2.9 g) purified by high-performance liquid chromatography (heterogeneous SiOH 20-45 μm, 450 g MATREX/mobile phase: 60% of cyclohexane, 40% EtOAc). Pure fractions are collected, the solvent is evaporated and receive 2 g of intermediate compound 33.

d) Obtaining an intermediate compound 34

To a solution of intermediate 33 (10 mmol) in CH2Cl2(20 ml) at room temperature is added dropwise periodinane dessa-Martin (24,9 ml). The reaction mixture was stirred at room temperature for 1 hour, then poured into a mixture of ice water, filtered through celite and the filtrate is extracted with CH2Cl2. The organic layer is separated, dried over MgSO4, filtered and the solvent evaporated. The residue (2.8 g) purified column chromatography on silica gel (eluent cyclohexane/EtOAc, 60/40). Pure fractions are collected, the solvent is evaporated and obtain 0.8 g of the intermediate compound 34.

e) Obtaining an intermediate compound 35

It races the thief intermediate 34 (4 mmol) in THF (15 ml) at 5°C in an atmosphere of N 2add dropwise methylmagnesium (12.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes. At 5°C. carefully add 10% aqueous solution of NH4Cl. Add EtOAc and the reaction mixture is extracted. The organic layer is separated, dried over MgSO4, filtered and evaporated. The residue (1.3 g) purified column chromatography (eluent cyclohexane/EtOAc, 70/30). Pure fractions are collected, the solvent is evaporated and obtain 0.8 g of the intermediate compound 35.

f) Obtaining an intermediate compound 36

A mixture of intermediate 35 (2.8 mmol) and Raney Nickel (0.6 g) in a solution of CH3HE/NH3(10 ml) hydronaut at a pressure of 3 bar at room temperature for 2 hours. The residue is filtered through celite, washed with CH2Cl2the solvent is evaporated and obtain 0.7 g of the intermediate compound 36.

g) Receiving the intermediate 37

A mixture of intermediate 36 (1,60 mmol), 2,3-debtor-6-nitroanisole (1,76 mmol) and sodium salt of carbonic acid (1.92 mmol) in DMSO (5 ml) and heat at 60°C over night. The mixture is cooled to room temperature. Add a mixture of water with ice. Add CH2Cl2. The reaction mixture was extracted and the organic layer is separated, dried over MgSO4, fil the shape and focus. The residue (0.8 g) purified by high-performance liquid chromatography (heterogeneous SiOH 15-40 μm, 300 g MERCK/mobile phase: 70% cyclohexane, 30% EtOAc). Pure fractions are collected, the solvent is evaporated and obtain 450 mg of the intermediate 37.

h) Obtaining an intermediate compound 38

Intermediate compound 37 (1,03 mmol), 5% Pt/C (0.1 g), V2O5(5 ml) and 4% solution of thiophene in DIPE (30 μl) in THF (20 ml) hydronaut at atmospheric pressure for 1 night at room temperature. The reaction mixture was filtered through celite, washed with CH2Cl2the filtrate is evaporated and obtain 0.33 g of the intermediate compound 38.

C. obtain the final compounds

Example B1

Obtaining the compound (11)

A mixture of intermediate compound 2 (0,0012 mol), hydrochloride 4-bromopyridine (1:1) (0,0012 mol) and DIPEA (0.001 mol) in CH3CN (10 ml) was stirred at 65°C for 18 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with a mixture of CH2Cl2/CH3IT (a little). The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0,47 g) purified column chromatography on a kromasil (eluent CH2Cl2/CH3HE/NH4OH, 97/3/0,3 to 91/9/0,9; 3, µm). Pure fractions are collected and the solvent is evaporated. The residue is crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding 0,163 g (36%) of compound (11) (TPL 164°C).

Compound No. 12, 13 and 65 receive according to example B1.

Example B2

a) Obtaining compound 3

A mixture of intermediate compound 4 (is 0.0002 mol), hydrochloride 4-bromopyridine (1:1) (is 0.0002 mol) and DIPEA (is 0.0002 mol) in CH3CN (1 ml) and EtOH (0.5 ml) was stirred at 65°C for 18 hours. Add 4 N. HCl (0.2 EQ.) in dioxane (14 ml). The mixture was stirred at 65°C for 18 hours, then cooled to room temperature, diluted with CH2Cl2and washed with 10% aqueous solution of K2CO3. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0.24 g) purified column chromatography on Sunfire (eluent CH2Cl2/CH3HE/NH4OH, from 100/0/0 to 93/7/0,7; 5 μm). Pure fractions are collected and the solvent is evaporated. The residue (0,073 g, 57%) crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding 0,039 g (30%) of compound 3 (TPL 187°C).

Connection # 4 receive according to example VI).

b) Receiving the connection 5

A mixture of intermediate compound 4 (is 0.0002 mol), 4-chloro-6,7-dihydro-5H-cyclopent[b]is iridin-7-ol (is 0.0002 mol) in 4 B.C. a solution of HCl/dioxane (14 ml), CH3CN (1 ml) and EtOH (0.5 ml) was stirred at 65°C for 18 hours. Add 4 N. HCl (0.2 EQ.) in dioxane (14 ml). The mixture was stirred at 65°C for 18 hours, then cooled to room temperature, diluted with CH2Cl2and washed with 10% aqueous solution of K2CO3. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0.14 g) purified column chromatography on Sunfire (eluent CH2Cl2/CH3HE/NH4OH, from 100/0/0 to 92/8/0,8; 5 μm). Pure fractions are collected and the solvent is evaporated. The residue (0,072 g, 50%) crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding 0,049 g (30%) of compound 5 (TPL 178°C).

Example B3

The connection 14

A mixture of intermediate compound 2 (0,0012 mol), 4-chloro-2-pyridinemethanol (0,0012 mol) and 4 n HCl/dioxane (is 0.0002 mol) in CH3CN (10 ml) was stirred at 65°C for 18 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with a mixture of CH2Cl2/CH3OH (a little). The organic layer is separated, dried (MgSO4), filtered and the solvent evaporated to dryness. The residue (0.52 g) purified column chromatography on a kromasil (eluent CH2Cl2/CH3OH/NH OH, 97/3/0,3 to 91/9/0,9; 3-5 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.3 g, 60%) crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding 0,292 g (51%) of compound 14 in the form of a hydrochloride salt (.1,52 HCl, TPL 110°C).

Compound No. 15, 16 and 60 receive according to example B3.

Example B4

a) Obtaining compounds 24

A mixture of intermediate compound 6A (0,0007 mol) and 4-chloro-2-pyridinemethanol (0,0007 mol) in 4 BC, the HCl/dioxane (0.0001 mol), CH3CN (2.5 ml) and EtOH (1 ml) was stirred at 65°C for 18 hours. The mixture is cooled to room temperature, diluted with CH2Cl2and washed with 10% aqueous solution of K2CO3. The organic layer is decanted, dried (MgSO4), filtered and the solvent is evaporated to 15 ml, the Residue is filtered off and dried, yielding has 0.168 g (64%) of compound 24 (TPL 115°C).

b) Obtaining compounds 25

A mixture of intermediate compound 6b (0,0007 mol) and 4-chloro-2-pyridinemethanol (0,0007 mol) in 4 BC, the HCl/dioxane (0.0001 mol), CH3CN (2 ml) and EtOH (0.8 ml) was stirred at 65°C for 18 hours. The mixture is cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with CH2Cl2. Precipitated precipitated substance is filtered off, washed with CH3CN, drying and receive 0,155 g (53%) of compound 25 (TPL 186°C).

Compound No. 26, 27 and 28 receive according to example B4b).

C) Obtaining connection 31

A mixture of intermediate compound 6C (0,0008 mol) and 4-chlorhydrin (0,0009 mol) in 4 BC, the HCl/dioxane (0.0001 mol), CH3CN (2.5 ml) and EtOH (1 ml) was stirred at 65°C for 48 hours. The mixture is cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with CH2Cl2. Precipitated precipitated substance is filtered off, washed with CH3CN, dried and receive 0,266 g (71%) of compound 31 (TPL 175°C).

Compound No. 29, 30 and 32 receive according to example Vs).

Example B5

The connection 17

A mixture of intermediate compound 2 (0,0012 mol), 4-chloro-6,7-dihydro-5H-cyclopent[b]pyridine-7-ol (0,0012 mol) and 4 n HCl/dioxane (0,0025 mol) in CH3CN (10 ml) was stirred at 65°C for 18 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with a mixture of CH2Cl2/CH3IT (a little). The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0.54 g) purified column chromatography on a kromasil (eluent CH2Cl2/CH3HE/NH4OH, 97/3/0,3 to 88/12/1,2; 3-5 μm). Pure fractions are collected and the solvent is evaporated. the STATCOM (0.14 g, 26%) crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding 0,113 g (21%) of compound 17 (TPL 147°C).

Connection№№ 18, 19, 20, 21, 22, 23, 33, 34, 35, 36, 37 and 61 receive according to example B5.

Example B6

a) Obtaining the compound (9)

A mixture of intermediate compound 8A (0,0006 mol) and 4-chloro-6,7-dihydro-5H-cyclopent[b]pyridine-7-ol (0,006 mol) in 4 BC, the HCl/dioxane (0.0001 mol), CH3CN (2 ml) and CH3OH (0.8 ml) was stirred at 65°C for 18 hours and then cooled at room temperature. Add 3 N. HCl (0,0025 mol). The mixture was stirred at 65°C for 18 hours, cooled at room temperature, diluted with CH2Cl2and washed with 10% aqueous solution of K2CO3. The organic layer is decanted, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0.36 g) purified column chromatography on a kromasil (eluent CH2Cl2/CH3HE/NH4OH, from 98/2/0,2 to 90/10/1; 3.5 µm). Pure fractions (0.14 g) crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding 0,120 g (47%) of compound (9) (TPL 207°C).

Compound No. 7 and 8 receive according to example VI).

b) Receiving connection 10

A mixture of intermediate compound 8b (0,0007 mol) and 4-chloro-6,7-dihydro-5H-cyclopent[b]feast the DIN-7-ol (0,0008 mol) in 4 B.C. a solution of HCl/dioxane (0.0001 mol), CH3CN (2 ml) and CH3OH (0.8 ml) was stirred at 65°C for 48 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with CH2Cl2. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated. The residue is purified column chromatography on a kromasil (eluent CH2Cl2/CH3HE/NH4OH, from 98/2/0,2 to 90/10/1; 3.5 µm). Pure fractions are collected and the solvent is evaporated to dryness. The residue is crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding to 0.055 g (17%) of compound 10 (TPL 237°C).

Example B7

The connection 53

A mixture of intermediate 11 (0,0011 mol), 4-chlorhydrin (0,0012 mol) and 4 n HCl/dioxane (is 0.0002 mol) in CH3CN (2.5 ml) and EtOH (1 ml) was stirred at 65°C for 18 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with CH2Cl2. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated. Precipitated precipitated substance is filtered off and dried, yielding 0,366 g (66%) of compound 53 (TPL 192°C).

Compound No. 51, 52, 53 and 54 receive according to example V7.

Example B8

The connection 59

A solution of intermediate 14 (of 0.0005 mol) in 3 BC HCl (5 ml) and THF (1 ml) was stirred at 100°C for 10 days. Add a 10% aqueous solution of K2CO3and CH2Cl2. The mixture is extracted. The organic layer is separated, dried (MgSO4), filtered and concentrated. The residue (0.2 g) purified column chromatography (eluent CH2Cl2/CH3HE/NH4OH, 93/7/0,1). The residue (0,010 g, 5%) purified column chromatography (eluent CH2Cl2/CH3HE/NH4OH, 93/7/0,7). Pure fractions are collected, the solvent is evaporated and get 0,003 g (1.5%) of compound 59.

Example B9

a) Obtaining compounds 1

A mixture of intermediate 16 (of 0.0005 mol), hydrochloride 4-bromopyridine (1:1) (of 0.0005 mol) and DIPEA (of 0.0004 mol) in CH3CN (1.5 ml) and EtOH (0.5 ml) was stirred at 65°C for 18 hours. Add 4 N. HCl (0.2 EQ.) in dioxane (29 ml). The mixture was stirred at 65°C for 18 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with EtOAc. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0.24 g) purified column chromatography on a kromasil (eluent CH2Cl2/CH3HE/NH4OH, 93/7/0,5; 10 μm). Pure fractions are collected, the solvent is evaporated and get 0,039 g (19%) soy is inania 1 (TPL 186°C).

b) Receiving connection 2

A mixture of intermediate 16 (of 0.0005 mol), 4-chloro-2-pyridinemethanol (of 0.0005 mol) and 4 n HCl/dioxane (0.0001 mol) in CH3CN (1.5 ml) and EtOH (0.5 ml) was stirred at 65°C for 18 hours. Add 4 N. HCl (0.2 EQ.) in dioxane (29 ml). The mixture was stirred at 65°C for 18 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with EtOAc. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0.18 g) purified column chromatography on silica gel (eluent CH2Cl2/CH3HE/NH4OH, 93/7/0,5; 10 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.03 g, 14%) crystallized from a mixture of CH3CN/DIPE. Precipitated precipitated substance is filtered off and dried, yielding 0.03 g (9%) of compound 2 (TPL 163°C).

Example 10

Obtaining compounds 55

A mixture of intermediate 18 (0,0008 mol) and hydrochloride of 4-bromopyridine (1:1) (0,0008 mol) in DIPEA (0,0006 mol), CH3CN (2.5 ml) and EtOH (1 ml) was stirred at 65°C for 18 hours, then cooled at room temperature, poured into 10% aqueous solution of K2CO3and extracted with CH2Cl2. The organic layer is decanted, dried (MgSO4), filtered and R is storytell is evaporated to dryness. The residue (0,357 g) purified column chromatography on silica gel (eluent CH2Cl2/CH3HE/NH4OH, 95/5/0,5; 15-40 μm). The solvent from the pure fractions are evaporated to dryness. The balance is 0.135 g) is crystallized from a mixture of CH3CN/EtOH/DIPE and get 0.126 g (35%) of compound 55 in the form of a hydrochloride salt (.0,99 HCl, TPL 245°C).

Compound No. 56, 57 and 58 receive according to example 10.

Example B11

The connection 50

A mixture of intermediate 20 (0.001 mol), hydrochloride 4-bromopyridine (1:1) (0.001 mol) and DIPEA (0,0008 mol) in CH3CN (2.5 ml) and EtOH (1 ml) was stirred at 65°C for 18 hours, then cooled to room temperature, poured into 10% aqueous solution of K2CO3and extracted with CH2Cl2. The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The remainder (0,37 g) purified column chromatography on a kromasil (eluent CH2Cl2/CH3HE/NH4OH, from 98/2/0,2 to 88/12/1,2; 3.5 µm). Pure fractions are collected and the solvent is evaporated to dryness. The residue is crystallized from CH3CN. Precipitated precipitated substance is filtered off and dried, yielding 0,095 g (23%) of compound 50 (TPL 241°C).

Example B12

The connection 49

A mixture of intermediate 22 (0,0015 mol) and 4-chloro-6,7-dihydro-5H-is clopant[b]pyridine-7-ol (0,0016 mol) in 4 B.C. a solution of HCl/dioxane (0,0003 mol), CH3CN (3 ml) and EtOH (1.2 ml) was stirred at 65°C for 18 hours, then cooled at room temperature, poured into 10% aqueous solution of K2CO3and extracted with CH2Cl2. The organic layer is decanted, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0.74 g) purified column chromatography on a kromasil (eluent CH2Cl2/CH3HE/NH4OH, from 100 to 93/7/0,7; 5 μm). The solvent is evaporated to dryness. The residue (0,445 g) crystallized from EtOH. The residue is filtered off and dried, yielding 0,244 g (36%) of compound 49 (TPL 123°C).

Connection№№ 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and 48 receive according to example B12.

Example B13

Getting connection 6

A mixture of intermediate 24 (0,0008 mol) and hydrochloride of 4-bromopyridine (1:1) (0,0008 mol) in DMF (3 ml) was stirred at 105°C for 1 hour and 30 minutes, then cooled to room temperature and poured into 10% aqueous solution of K2CO3. Precipitated precipitated substance is filtered off, washed with water several times and dissolved in a mixture of CH2Cl2/CH3IT (a little). The organic layer is separated, dried (MgSO4), filtered and the solvent is evaporated to dryness. The residue (0,38 g) purified column chromatography on a kromasil (eluent CH2Cl2/CH3HE/NH 4OH, 96/4/0,4 to 88/12/1,2; 5 μm). Pure fractions are collected and the solvent is evaporated. Crude oil (0.09 g, 23%) was dissolved in isopropanol and cooled in an ice bath. Add 5 n HCl/isopropanol (2 EQ.). Precipitated precipitated substance is filtered off and dried, yielding 0,063 g (16%) of compound 6 (TPL 166°C).

Example B14

The connection 62

To a solution of intermediate compound 30 in THF at 5°With add on parts 1 M solution of lithium aluminum hydride in THF (0,398 mmol). The mixture is stirred for 2 hours at room temperature. Gently at 5°C. add water. Add EtOAc. The reaction mixture was filtered through celite and extracted. The organic layer is separated, dried over MgSO4filter and concentrate. The crude compound (0.12 g) purified column chromatography on silica gel (eluent CH2Cl2/CH3HE/NH4OH, 95/5/0,5; 30 g 15-40 μm). Pure fractions are collected, the solvent is evaporated and get 0,042 g of compound 62.

Example B15

Obtaining compounds 63 and 64

and

the connection 63 and the connection 64

A solution of intermediate 38 (to 0.92 mmol), 4-chloro-6,7-dihydro-5H-cyclopent[b]pyridine-7-ol (1 mmol) and 4 M solution of hydrogen chloride in dioxane (46 ml) in CH3CN (10 ml) and heat at 65°C for 5 h the owls. Add a 10% aqueous solution of K2CO3and EtOAc. The reaction mixture was extracted, the organic layer is separated, dried over MgSO4, filtered and evaporated. The residue (0.4 g), purified by high-performance liquid chromatography (homogeneous silica, 5 μm, 150×30.0 mm; mobile phase of 0.2% NH4OH; the gradient of CH2Cl2/CH3HE is from 98/2 to 88/12) and obtain 49 mg of compound 63 and 114 mg of compound 64.

C. Pharmacological example

Cells A are cell carcinoma of the ovary of a man with wild type p53.

The ability of compounds to keep p53 in cells A can be measured enzyme-linked immunosorbent assay p53 (ELISA). Analysis of p53 is a sandwich enzyme linked immunosorbent assay using two types of polyclonal antibodies. Polyclonal antibodies specific for the protein p53, immobilized on the surface of plastic wells. Any of p53 present in the analyzed sample will bind to the immobilized antibodies. Biotinylated detector polyclonal antibodies recognize protein p53 and will contact any of p53, which withheld the immobilized antibody. The detector antibody, in turn, linked by streptavidin, conjugated to horseradish peroxidase. Horseradish peroxidase catalyzes the conversion of the chromogenic substrate o-phenylenediamine, intensive the awn which is proportional to the amount of p53 protein, associated with the tablet. The colored reaction product is determined quantitatively using a spectrophotometer. Quantitative determination reached by constructing a standard curve using known concentrations of purified recombinant p53 protein, labeled with HIS (see figure C.1).

Using colorimetric analysis on tumor cells A determine the cellular activity of the compounds of formula (I) at the cellular toxicity or survival (see figure C.2).

C.1. ELISA p53

Cells A cultivated in RPMI 1640 with the addition of 10% fetal calf serum (FCS), 2 mm L-glutamine and gentamycin at 37°C in a humid chamber with 5% CO2.

Cells A seeded in 96-well tablets at 20,000 cells per well, cultured for 24 hours and treated with compound for 16 hours at 37°C in a humid chamber. After incubation, the cells washed once with phosphate buffered saline and add 30 ál per well of RIPA buffer with low salt (20 mm Tris, pH 7.0, 0.5 mm add, 1% nonidet R40, of 0.5% DOC, 0.05% of SDS, 1 mm PMSF, 1 μg/ml Aprotinin and 0.5 μg/ml leupeptin). The tablets are placed on ice for 30 minutes for complete lysis. P53 protein detected in the lysates using the sandwich ELISA described below.

Sensibiliser 96-well tablets of highly-binding polystyrene EIA/RIA (Costar 9018) is immobilizovannymi antibody pAb1801 (Abcam ab28-100) at a concentration of 1 μg/ml in buffer for sensitization (0.1 M NaHCO 3pH of 8.2), 50 μl per well. The antibodies provide an opportunity to adhere overnight at 4°C. Sensitized tablets washed once with phosphate buffered saline (PBS)/0.05% tween-20, add 300 μl of blocking buffer (PBS, 1% bovine serum albumin (BSA)and incubated for 2 hours at room temperature. Get breeding purified recombinant p53 protein, labeled with HIS, in the range of 3-200 ng/ml in blocking buffer and used as standards.

Tablets twice washed with PBS/0.05% tween-20 and add blocking buffer or standards at 80 μl/well. The standards add 20 ál of buffer for lysis. Samples added to other wells in 20 μl of lysate per well. After incubation over night at 4°C, tablets, twice washed with PBS/0.05% tween-20. Aliquot 100 μl of the second polyclonal antibodies to p53 (FL-393) (Tebubio, sc-6243) at a concentration of 1 μg/ml in blocking buffer is added to each well and leave for adhesion for 2 hours at room temperature. Tablets washed three times with PBS/0.05% tween-20. Add anti-rabbit antibody with HRP for detection (sc-2004, Tebubio) at a concentration of 0.04 µg/ml in PBS/1% BSA and incubated for 1 hour at room temperature. Tablets washed three times with PBS/0.05% tween-20 and add 100 ál of buffer substrate buffer (buffer for substrate obtained directly applied before the eat, adding 1 tablet 10 mg o-phenylenediamine (OPD) from Sigma and 125 μl of 3% H2About2to 25 ml of buffer OPD: 35 mm citric acid, 66 mm Na2HPO4pH of 5.6). After 5-10 minutes the color reaction is stopped by adding 50 μl of stop buffer (1 M H2SO4) per well. The absorption at two wavelengths 490/655 nm was measured using a microplate reader (Biorad, and then analyze the results.

For each experiment together with the incubation of the control (containing no drug) and pacifiers (containing no cells or drugs). The value for dummy subtracted from the values of all specimens and controls. For each sample size for p53 (in units of absorption) is expressed as the percentage of values for p53 present in the control. Save percentage over 140% identify as significant. In this case, the effect of the test compounds is expressed as the lowest dose that gives at least 140% of the value for p53 present in the control (see table 3 below).

In some experiments, the analysis will be adjusted for the use of 384-well culture plates.

40
Table 3
The results for compounds which have the above-mentioned ELISA Protocol p53 (cell A)
Connection # p53-elisa LAD [Microm]Connection # p53-elisa LAD [Microm]
1>10,0333,0
23,0341,0
3>10,0351,0
4>10,03610,0
50,3373,0
61,0383,0
7>10,0390,1
8>10,01,0
9>10,0410,3
101,0420,1
11>10,0430,3
1210,0441,0
13>10,0451,0
14>10,0461,0
15>10,0470,1
16>10,0481,0
171,0 491,0
18>10,050>10,0
19>10,051>10,0
20>10,052>10,0
21>10,053>10,0
22>10,054>10,0
23>10,055>10,0
24>10,056>10,0
253,057>10,0
26>10,058>10,0
27>10,059-
28>10,060>10,0
291,0610,3
301,0623,0
311,0631,0
32>10,0640,3
65>10,0

C.2. Analysis of cell proliferation

Cells human glioma U87MG cultured in DMEM with addition of 2 mm L-glutamine, 1 mm feast the ATA sodium, 1.5 g/l sodium bicarbonate, 50 µg/ml gentamicin and 10% V / V heat inactivated fetal calf serum. (U87MG cells are cells in human glioblastoma with wild type p53. In this cell line MDM2 strictly regulates the expression of p53.)

Cancer cells of human ovarian A kindly donated by Dr. T.C. Hamilton (Fox Chase Cancer Centre, Pennsylvania, USA). Cells were cultured in medium RPMI 1640 with the addition of 2 mm L-glutamine, 50 μg/ml gentamicin and 10% fetal calf serum.

The reagents used in the assay with Alamar Blue

Resazurin purchased from Aldrich (prod. No. 199303). The potassium ferrocyanide, potassium ferricyanide, KN2RHO4and K2NRA4purchased from Sigma (prod. No. R, R, R and R respectively).

Califofnia buffer (eres), 0.1 M, was obtained as follows: 2,72 g KN2RHO4and 13,86 g K2NRA4dissolved in 500 ml deionized (milli Q) water, adjusted pH to 7.4 and bring volume to 1 l of deionized water; buffer is sterilized by filtration and stored at room temperature. The original solution of resazurin (eres, And get fresh, dissolving 45 mg of resazurin in 15 ml PBS. A solution of 30 mm potassium ferricyanide (eres) receive, dissolving 0,987 g of potassium ferricyanide in 100 ml of PPB. A solution of 30 mm potassium ferrocyanide (eres) receive, dissolving 1,266 g of potassium ferrocyanide in 100 ml of PPB.

The mixture eres, eres-and ERE-To receive, mixing RA is ing amounts of the respective solutions. The working solution of resazurin (called in this case the solution "Alamar Blue") receive, diluting this mixture 20× (./about.) in eres, and sterilizing filtration; Alamar Blue solution can be stored at 4°C for up to 2 weeks.

The analysis procedure with Alamar Blue

For experiments in 384-well tablets seeded cells at a density of 5×103cells/ml in 45 ál of culture medium to dark culture 384-well tablets-bottomed Falcon (Life Technologies, Merelbeke, Belgium). The cells are allowed to adhere to plastic for 24 hours. The test compound is pre-diluted (1/50 in culture medium) and in wells add 5 ál of pre-diluted compounds. After 4-day incubation, each well add 10 μl of Alamar Blue solution and the cells incubated for another 5 hours (A) or 6 hours (U87MG) at 37°C. the fluorescence Intensity was measured for each well by fluorometer for reading tablets (Fluorskan, Labsystems, excitation at 540 nm, emission at 590 nm).

Antiproliferative activity is calculated as the percentage of cells remaining viable in the treatment versus control (untreated cells). In the experiment, the result for each condition processing is the average of results for 3 re-holes. In appropriate cases, the repeat experiments in order to install the data curves depending on the concentration. As appropriate, the value of the IC50(the concentration of drug required to reduce cell growth by 50% of control) is calculated using probit analysis for step data (Finney D.J., Probit analysis, 2nded., Chapter 10, Graded Responses, Cambridge University Press, Cambridge, 1962). In this description, the effect of the test compounds is expressed as the pIC50(the negative log of the value of the IC50) (see table 4).

td align="center"> <5
Table 4
The results for compounds which have the above Protocol cell proliferation
Connection # Inhibition of cell proliferation A
pIC50
The inhibition of proliferation of U87MG cells
pIC50
Connection # Inhibition of cell proliferation A
pIC50
The inhibition of proliferation of U87MG cells
pIC50
1<5<533<5<5
2 <55,11345,675,14
3<5<535<5<5
4<5<536<55,08
5<5<537<5<5
6<55,8038~5,23the 6.06
75,08<539~5,596,07
8<55,41 40~5,195,86
95,38<5415,38of 5.83
10the 5.455,55426,156,75
11<55,31435,56of 5.81
12<55,6244~5,966,56
13<55,18456,396,14
14<5<546 ~5,46between 6.08
15<5~5,2347~5,746,35
16<5<548<55,26
175,085,16496,30to 6.19
18<55,1750<5<5
19<55,1551<55,20
20<5<552<55,33
21<5<553<5of 5.40
22<5of 5.2954<5-
23<5<555<5<5
24<5<556<5-
25<5<557<5<5
26<5<558<5<5
27<5 <559--
28<5<560<55,18
295,58<561<55,23
305,08of 5.06626,04of 5.89
31~5,595,88637,136,33
32<55,48647,076,47
655,26
~ means approximately

D. Analytical data

The General procedure of liquid chromatography (LC)

The dimension LC carried out using UPLC (ultra-efficient liquid chromatography) Acquity (Waters), including a dual pump apparatus for obezvozhivanija, auto sampler, a detector with diode array (DAD) and a column is described below in appropriate ways, the column was kept at 40°C. Flow from the column enters the MS detector. MS-detector packaged with a source of spray ionization electrons. The voltage on the capillary needle 3 kV, and support the source temperature 130°C in Quattro (triple quadrupole mass spectrometer from Waters). As a gas atomizer using nitrogen. Data collection is performed using the data system Waters-Micromass MassLynx-Openlynx.

In addition to the above procedure. UPLC with reversed phase carried out on a column Waters Acquity VEINS (hybrid bridge etisalats/silicon dioxide) with a C18 (1.7 mm, and 2.1×100 mm) at a flow rate of 0.35 ml/min Using two mobile phases (mobile phase A: 95% 7 mm ammonium acetate/5% acetonitrile; mobile phase b: 100% acetonitrile) to pass in conditions with a gradient from 90% a and 10% B (shutter speed for 0.5 minutes) to 8% And I% In 3.5 minutes exposure for 2 min and return to initial conditions for 0.5 min shutter speed for 1.5 minutes. Use a volume of 2 μl injection. The voltage on the cone 20 for ionization in positive and negative type. The mass spectrum is obtained by scanning from 100 to 1000 in 0.2 seconds using the delay between scans 0.1 seconds.

Table 5
Analytical data JHMS: Rtrepresents the retention time in minutes; [MH]+means the protonated mass of the compound
Connection # Rt[MH]+
599.28 are411
622,91463
633,23491
643,72473

That is an Example of the composition: tablets film coated

Obtain core tablets

A mixture of 100 g of compound of formula (I), 570 g lactose and 200 g starch are thoroughly mixed and then moisturize with a solution of 5 g Daudet is inculpate sodium and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then there was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All are thoroughly mixed and pressed into tablets, get 10,000 tablets, each contains 10 mg of the compounds of formula (I).

Coating

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then to the mixture is added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the first, then added to the mixture of 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye and all homogenized. The core tablets are coated with the thus obtained mixture in a machine for coating.

1. The compound of formula (I)

where m is 0, 1 or 2, and when m is 0, this then implies a direct link;
n is 0, 1, 2 or 3, and when n is 0 then implies a direct link;
p is 0 or 1, and when p is 0, this then implies a direct link;
s is 0 or 1 and when s is 0, this then implies a direct link;
t is 0 or 1, and when t is 0, this then implies a direct link;
X represents CHR8 where
R8represents hydrogen;
represents-CR9=C<, and then the dotted line represents a bond, R9represents independently hydrogen or C1-6-alkyl, or where R9together with one of R2or R20forms a direct link;
R1represents hydrogen;
R2and R20choose each independently of the
halogen, cyano;
polyhalogen-C1-6-alkyl;
C1-6-alkyl, morpholinyl,1-6-alkyloxy, and any of these groups optionally and independently substituted by hydroxy; and
NR21R22where
R21and R22choose each independently hydrogen, C1-6-alkylcarboxylic;
or R21and R20together with the phenyl cycle to which they are attached, form naphthalenyloxy group;
or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct link;
R3represents hydrogen;
R4and R5are each independently hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6alkenyl or1-6-alkyloxy; or
R6represents hydrogen;
when p is equal to 1, then R7represents hydrogen;
Z represents a radical selected from

where R10or R11choose each independently hydrogen, hydroxy, hydroxy-C1-6-alkyl.

2. The compound according to claim 1, in which
R4and R5are each independently hydrogen, C1-6-alkyl, C1-6-alkyloxy.

3. The compound according to claim 1, in which
s is 0; t is 0; m is 0; p is 0; n is 1 or 2; X represents CH2.

4. The compound according to claim 1, in which R2and R20choose each independently from halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy, hydroxyl-C1-6-alkyl, -NR21R22where R21represents hydrogen, and R22represents a C1-6-alkylsulphonyl; or R2and R20together with the phenyl cycle to which they are attached, form naphthalenyloxy group, or one of R2or R20has the values listed above, and the other of R2or R20together with R9forms a direct connection.

5. The compound according to claim 1, selected from the following groups:

6. The compound according to any one of claims 1 to 5 for use as a medicine.

7. Pharmaceutical composition having inhibitory activity against the interaction between MDM2 and p53, including pharmaceutically pickup is acceptable carriers and as active ingredient a therapeutically effective amount of a compound according to claims 1-5.

8. The use of compounds according to any one of claims 1 to 5 to obtain drugs for the treatment of disorders mediated by the interaction of the p53-MDM2.

9. The use of compounds according to any one of claims 1 to 5 to obtain drugs for cancer treatment.

10. The use according to claim 9, where the cancer is a breast cancer, colorectal cancer, non-small cell lung cancer or acute myeloid leukemia.

11. A method of obtaining a compound according to claim 1, characterized
a) interaction of the intermediate compounds of formula (IV) with an intermediate compound of formula (V)in which W represents a reasonable delete group

where the variables have the meanings indicated in claim 1, and where W represents a halogen.

12. A method of obtaining a compound according to claim 1, characterized by the interaction of the intermediate compounds of formula (XXIV) with lithium aluminum hydride in a suitable solvent to form compounds of formula (I), where R4represents-CH2HE called in this case compounds of the formula (I-e)

where the variables have the meanings indicated in claim 1.

13. A method of obtaining a compound according to claim 1, characterized by the conversion of intermediate compounds of formula (XIX) in the presence of a strong acid in a suitable solvent with the formation of the connection the settings of the formula (III)

where the variables have the meanings indicated in claim 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, to a based composition, the use of said crystalline form 1, methods for preparing it.

EFFECT: what is prepared is the new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide effective for treating cancer.

10 cl, 9 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

,

where X1 denotes a bond, NR8 or S; Y1 denotes O or NR ; R1 denotes C1-10alkyl, C6-10aryl or a 5-10-member heteroaryl containing 1-3 heteroatoms which are independently selected from N or S; where said R1 is optionally substituted with 0-2 J1; R2 denotes H or C1-10alkyl; each of R3, R4, R5 and R6 independently denotes H or C1-10alkyl; and R7 denotes C1-10alkyl, C3-10cycloalkyl, phenyl, 5-6-member heterocyclyl containing 1-3 heteroatoms independently selected from O and N, - (C1-6alkyl) -(C3-10cycloalkyl), - (C1-6alkyl) - (phenyl) or -(C1-6alkyl)-(6-member heterocyclyl containing 2 heteroatoms selected from O and N); where said R7 is optionally substituted with 0-5 J7; or R3 and R4, together with a carbon atom with which they are bonded, optionally form a 3-4-member saturated or partially unsaturated monocyclic fragment; R3 and R5, together with carbon atoms with which they are bonded, optionally form a 5-member monocyclic fragment; R8 denotes H; R9 denotes H or unsubstituted C1-6alkyl; or R2 and R9, together with atoms with which they are bonded, optionally form a 5-member aromatic monocyclic fragment containing 3 nitrogen atoms; each J1 independently denotes C1-6halogenalkyl, halogen, NO2, CN, Q or -Z-Q; or two J1 together can optionally form =O; Z denotes C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -NR-, -O-, -C(O)- or -SO2-; wherein each Z is optionally substituted with 0-2 J2; Q denotes H; C1-6alkyl; 3-8-member aromatic or non-aromatic monocyclic fragment containing 0-3 heteroatoms independently selected from O, N and S; or an 8-10-member aromatic bicyclic system; each Q is optionally substituted with 0-2 JQ; each J7 independently denotes C1-6alkyl or halogen(C1-4alkyl); each of JQ and J7 independently denotes M or -Y-M; each Y independently denotes an unsubstituted C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -O-, -C(O)- or -SO2-; each M independently denotes H, C1-6alkyl, C3-6cycloalkyl; halogen (C1-6alkyl), phenyl, halogen, CN, OH, OR1; or two M together can optionally form =O; R denotes H or an unsubstituted C1-6alkyl; R' denotes an unsubstituted C1-6alkyl. The invention also relates to methods of producing said compounds and a pharmaceutical composition for inhibiting PLK based on said compounds.

EFFECT: novel compounds which can be used in medicine as inhibitors of protein kinase are obtained.

34 cl, 1 tbl, 279 ex

FIELD: chemistry.

SUBSTANCE: method involves heating cyclic thiourea at temperature from higher than 200°C to 250°C in a solvent which is selected from ethers, alcohols or mixtures thereof, to form bicyclic guanidines.

EFFECT: method enables to obtain a product with high output.

13 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heterocyclic amide compound of formula I: or a pharmaceutically acceptable salt thereof. Described also is a pharmaceutical composition containing said compound, having protein kinase inhibitor, regulator or modulator properties, which is acceptable in treating or preventing a proliferative disease, an anti-proliferative disorder, inflammation, arthritis, neurologic or neurodegenerative disease, cardiovascular disease, hair loss, neural disease, ischemic disorder, viral disease or fungal disease.

EFFECT: high efficiency of using the compounds.

2 cl, 20 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of formula (I) and pharmaceutically acceptable salts and solvates thereof, having IGF-IR and IR inhibiting properties, which can be used to treat proliferative cancerous diseases such as breast cancer, sarcoma, lung cancer and prostate cancer. In the compound of formula (I): R1 is selected from H and C1-C3alkyl; R2 is selected from H, C1-C3alkyl and halogen; R3 is selected from H, OH, C1-C6alkyl, groups -C1-C6alkylene-OH, -C1-C6alkylene-phenyl (optionally substituted with a halogen) and -C1-C6alkylene-C(O)NH2; R4 is selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl; or R3 and R4, together with atoms with which they are bonded, form a 5- or 6-member lactam; each of R5 and R6 is independently selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl, or R5 and R6 together with an aryl with which they are bonded form naphthalene; R7 is selected from C1-C6alkyl, -O-C1-C6alkyl, halogen, -N-R19R19 and -O-C1-C6alkylene-halogen; R8 is selected from H, halogen and C1-C6alkyl; one of R9 and R10 is selected from -C1-C6alkylene-SO2-C1-C6alkyl, -NR19-C(O)-C0-C6alkylene-NR22R23, -O- C0-C6alkylene(optionally substituted with -OH)-NR22R23, and etc, given in the claim and the other of R9 and R10 is selected from H, C1-C6alkyl, -O- C1-C6alkyl and halogen.

EFFECT: improved method.

41 cl, 12 dwg, 263 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a folate receptor ligand which is folate-polyethylene glycol-dihexadecyl-L-glutamate of formula and a method for production thereof. This compound exhibits the capacity to direct a nanosystem to target cells and increases the efficiency of transportation systems of antitumour agents since folate receptors are present in large amounts on the surface of tumour cells; also they become more at the later stages of development of the disease.

EFFECT: use of an approach based on click-chemistry principles for synthesis of a folate-targeted derivative provides a unique opportunity for fast and efficient modification of nanosystems.

2 cl

FIELD: chemistry.

SUBSTANCE: invention relates to biologically active compounds, specifically to a group of 2-substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones of general formula where R denotes hydrogen, a straight or branched (C1-C4)-alkyl; a hydroxyalkyl having an alkyl chain with 2-3 C atoms; a phenylalkyl having an alkyl chain with 1-2 C atoms, wherein the phenyl ring can have one or two methoxy groups. The invention also relates to a method of producing said compounds.

EFFECT: novel compounds can be used in medicine as antidepressant and antianxiety agents.

6 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: compound is a pyrrolidine derivative having a fragment of a sterically hindered phenol, having general formula: where R1 denotes H, Me, Et; R2 denotes Me, Et, i-Pr, i-Bu; Ar denotes Ph, 2-HalPh, 3-HalPh, 4-HalPh, (where Hal denotes F, Cl, Br, I), 2,6-diMePh, 2,3,5,6-tetraFPh, 2-MeOPh, 3-MeOPh, 4-MeOPh, (naphthalen-1-yl), (naphthalen-2-yl), 2-NO2PH, 3-NO2Ph, 4-NO2Ph. The compounds are obtained by mixing a solution of azomethine of formula: where values of R1, R2 are given above, with N-substituted malemide in air and reaction thereof is induced by catalytic amounts of N-tert-butoxycarbonyl derivatives of alpha-amino acids (glycine, alanine, phenylalanine), followed by concentration of the organic phase at low pressure, and cleaning the residue by chromatography on silica gel using CHCl3/MeOH as the eluent.

EFFECT: prolonged antioxidant activity.

2 cl, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing heterocycle-substituted pyridine derivatives of general formula (I) by reacting a compound of general formula (III) with a compound of formula (II) in a solvent and in the presence of a catalyst based on palladium or a base, where R1, R2, X, Y, Q, A, Z, R, R3 and R4 are described in the claim.

EFFECT: method enables to obtain pyridine derivatives on an industrial scale.

7 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a mTOR kinase inhibitor. In formula (I): A represents a 6-8-member mono- or bicyclic heterocyclic ring containing 1 to 2 heteroatoms optionally specified in N and O as apexes of the ring and having 0-2 double bonds; and wherein the ring A is additionally substituted by 0 to 2 substitutes RA specified in a group consisting of -ORa, -Rc and -(CH2)1-4-ORa wherein Ra is optionally specified in hydrogen and C1-6alkyl; Rc represents C1-6alkyl; G is specified in a group consisting of -C(O)-, -OC(O)-, -NHC(O)- and -S(O)0-2-; B is specified in a group consisting of phenylene and 5-6-member heteroarylene consisting 1-2 nitrogen heteroatom as apexes of the ring, and substituted by 0 to 1 substitutes RB specified in F, Cl, Br, I and Rp; wherein Rp represents C1-6 alkyl; D is specified in a group consisting of -NR3C(O)NR4R5, -NR4R5, C(O)NR4R5, -NR3C(=N-CN)NR4R5, -NR3C(O)R4, -NR3C(O)OR4 and -NR3S(O)2R4, and wherein the group D and a substitute placed on an adjoining atom in the ring B, optionally combined to form a 5-6-member heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms specified in N, O and S, as apexes of the ring and substituted by the substitute 0-1 RD. The R1-R5 radical values are presented in the patent claim.

EFFECT: invention also refers to a pharmaceutical composition containing said compounds, and to the use of the compounds for preparing a drug for treating a malignant tumour mediated by mTOR kinase activity.

33 cl, 13 dwg, 4 tbl, 498 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is 7-methyl-5-(3-piperazin-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having potentiating activity on glutamate receptors, containing the compound described above; also described is use of the compound or a pharmaceutically acceptable salt in claim 1 in producing a medicinal agent for therapy of neurological and mental disorders associated with glutamate dysfunction.

EFFECT: novel compound which can be used in therapy of neurological and mental disorders is obtained and described.

5 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II , where Q is (CR4R5)n3; n1 equals 1 or 2; n2 equals 1 or 2; n3 equals 1; R2 is R2-1 or R2-2 , Ar is phenyl or a heteroaryl ring consisting of 8-10 carbon atoms and 1-2 heteroatoms selected from O or S; X denotes 1-2 substitutes located on Ar, each independently selected from a group consisting of OR8, NR8R9, SR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9 and CN; R3-R5 denote H; R8 is H, alkyl, cyclopropyl, phenyl or pyridinyl; optionally substituted with one or more halogens or heteroatom-containing substitutes selected from a group consisting of OR11, NR11R12, CO2R11, CONR11R12, NRnC(=O)Ri2; R9 is H or alkyl; R11-R12 independently denote H, alkyl, pyridinyl or morpholinyl.

EFFECT: compounds are inhibitors of rho-associated protein kinase which can be used in medicine to prevent or treat diseases or conditions associated with cytoskeleton readjustment, specifically treat high intraocular pressure such as primary open angle glaucoma.

10 cl, 3 tbl, 226 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

Up!